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Sample records for beagle-based canine x-linked

  1. Comparative mapping of canine and human proximal Xq and genetic analysis of canine X-linked severe combined immunodeficiency

    SciTech Connect

    Deschenes, S.M.; Puck, J.M.; Dutra, A.S.

    1994-09-01

    Parallel genetic analysis of animal and human genetic diseases can facilitate the identification and characterization of the causative gene defects. For example, canine X-linked severe combined immunodeficiency (SCID) is characterized by clinical, pathological, and immunological manifestations similar to the most common form of human SCID. To derive a canine syntenic map including genes that in humans are located in proximal Xq, near human X-linked SCID, poly (TG) polymorphisms were identified at the canine phosphoglycerate kinase (PGK) and choroideremia (CHM) loci. These plus a polymorphic poly (CAG) sequence in exon 1 of the canine androgen receptor gene (AR) were used to genotype members of the colony informative for X-linked SCID. No recombinations among SCIDX1, AR, PGK, or CHM were observed. Fluorescence in situ hybridization localized PGK and CHM to proximal Xq in the dog, in the same chromosomal location occupied by the human genes. Somatic cell hybrid analysis and methylation differences at AR demonstrated that female dogs carrying X-linked SCID have the same lymphocyte-limited skewed X-chromosome inactivation patterns as human carriers. These genetic and phenotypic findings provide evidence that mutations in the same gene, now identified as the {gamma} chain of the IL-2 receptor, cause canine and human X-linked SCID. This approach is an efficient method for comparative gene mapping and disease identification. 35 refs., 4 figs., 1 tab.

  2. XLPRA: A canine retinal degeneration inherited as an X-linked trait

    SciTech Connect

    Acland, G.M.; Blanton, S.H.; Hershfield, B.; Aguirre, G.D.

    1994-08-01

    Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission. This dog was outcrossed to three phenotypically normal female laboratory Beagles and two of their F1 daughters were bred to a phenotypically normal male Beagle, producing affected males in the F2 generation. Subsequent inbreedings produced further affected males and affected females as well. X-linked transmission was established by exclusion of alternative modes of inheritance and, consequently, the disease has been termed X-linked progressive retinal atrophy (XLPRA). This is the first reported X-linked retinal degeneration in an animal. Because of the many similarities of PRA in dogs to retinitis pigmentosa (RP) in humans, this new disease may not only represent the first animal model of X-linked RP (XLRP) but may well be a true homolog of one of the XLRP loci (RP2, RP3, RP6). It is the first retinal degeneration in dogs that can be assigned to an identified canine chromosome, and the first for which linkage mapping offers a realistic approach to proceed by positional cloning towards identifying the responsible gene. 58 refs., 1 fig., 3 tabs.

  3. XLPRA: a canine retinal degeneration inherited as an X-linked trait.

    PubMed

    Acland, G M; Blanton, S H; Hershfield, B; Aguirre, G D

    1994-08-01

    Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission. This dog was outcrossed to three phenotypically normal female laboratory Beagles and two of their F1 daughters were bred to a phenotypically normal male Beagle, producing affected males in the F2 generation. Subsequent inbreedings produced further affected males and affected females as well. X-linked transmission was established by exclusion of alternative modes of inheritance and, consequently, the disease has been termed X-linked progressive retinal atrophy (XLPRA). This is the first reported X-linked retinal degeneration in an animal. Because of the many similarities of PRA in dogs to retinitis pigmentosa (RP) in humans, this new disease may not only represent the first animal model of X-linked RP (XLRP) but may well be a true homolog of one of the XLRP loci (RP2, RP3, RP6). It is the first retinal degeneration in dogs that can be assigned to an identified canine chromosome, and the first for which linkage mapping offers a realistic approach to proceed by positional cloning towards identifying the responsible gene locus.

  4. Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy

    PubMed Central

    Kuraoka, Mutsuki; Lee, Joshua J.A.; Takeda, Shin'ichi; Yokota, Toshifumi

    2016-01-01

    Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic diseases worldwide, caused by mutations in the dystrophin (DMD) gene. Exon skipping employs short DNA/RNA-like molecules called antisense oligonucleotides (AONs) that restore the reading frame and produce shorter but functional proteins. However, exon skipping therapy faces two major hurdles: limited applicability (up to only 13% of patients can be treated with a single AON drug), and uncertain function of truncated proteins. These issues were addressed with a cocktail AON approach. While approximately 70% of DMD patients can be treated by single exon skipping (all exons combined), one could potentially treat more than 90% of DMD patients if multiple exon skipping using cocktail antisense drugs can be realized. The canine X-linked muscular dystrophy (CXMD) dog model, whose phenotype is more similar to human DMD patients, was used to test the systemic efficacy and safety of multi-exon skipping of exons 6 and 8. The CXMD dog model harbors a splice site mutation in intron 6, leading to a lack of exon 7 in dystrophin mRNA. To restore the reading frame in CXMD requires multi-exon skipping of exons 6 and 8; therefore, CXMD is a good middle-sized animal model for testing the efficacy and safety of multi-exon skipping. In the current study, a cocktail of antisense morpholinos targeting exon 6 and exon 8 was designed and it restored dystrophin expression in body-wide skeletal muscles. Methods for transfection/injection of cocktail oligos and evaluation of the efficacy and safety of multi-exon skipping in the CXMD dog model are presented. PMID:27285612

  5. Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy.

    PubMed

    Miskew Nichols, Bailey; Aoki, Yoshitsugu; Kuraoka, Mutsuki; Lee, Joshua J A; Takeda, Shin'ichi; Yokota, Toshifumi

    2016-01-01

    Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic diseases worldwide, caused by mutations in the dystrophin (DMD) gene. Exon skipping employs short DNA/RNA-like molecules called antisense oligonucleotides (AONs) that restore the reading frame and produce shorter but functional proteins. However, exon skipping therapy faces two major hurdles: limited applicability (up to only 13% of patients can be treated with a single AON drug), and uncertain function of truncated proteins. These issues were addressed with a cocktail AON approach. While approximately 70% of DMD patients can be treated by single exon skipping (all exons combined), one could potentially treat more than 90% of DMD patients if multiple exon skipping using cocktail antisense drugs can be realized. The canine X-linked muscular dystrophy (CXMD) dog model, whose phenotype is more similar to human DMD patients, was used to test the systemic efficacy and safety of multi-exon skipping of exons 6 and 8. The CXMD dog model harbors a splice site mutation in intron 6, leading to a lack of exon 7 in dystrophin mRNA. To restore the reading frame in CXMD requires multi-exon skipping of exons 6 and 8; therefore, CXMD is a good middle-sized animal model for testing the efficacy and safety of multi-exon skipping. In the current study, a cocktail of antisense morpholinos targeting exon 6 and exon 8 was designed and it restored dystrophin expression in body-wide skeletal muscles. Methods for transfection/injection of cocktail oligos and evaluation of the efficacy and safety of multi-exon skipping in the CXMD dog model are presented. PMID:27285612

  6. Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3).

    PubMed

    Zeiss, C J; Ray, K; Acland, G M; Aguirre, G D

    2000-03-01

    X-linked progressive retinal atrophy (XLPRA) in the Siberian husky dog is a naturally occurring X-linked retinopathy closely resembling X-linked retinitis pigmentosa (XLRP) in humans. In affected males, initial degeneration of rods is followed by cone degeneration and complete retinal atrophy; carrier females have random patches of rod degeneration consistent with random X chromosome inactivation. By typing the XLPRA pedigree with five intragenic markers [dystrophin, retinitis pigmentosa GTPase regulator ( RPGR ), tissue inhibitor of metalloproteinases 1, androgen receptor and factor IX], we established a linkage map of the canine X chromosome, and confirmed that the order of these five genes is identical to that on the human X. XLPRA was tightly linked to an intragenic RPGR polymorphism (LOD 11.7, zero recombination), thus confirming locus homology with RP3. We cloned the full-length canine RPGR cDNA and three additional splice variants. No disease-causing mutation was found in the RPGR-coding sequence of the four splice variants characterized, a finding similar to approximately 80% of human XLRP patients whose disease maps to the RP3 locus. In addition, there were no significant differences in the proportional expression of each splice variant in normal and pre-degenerate XLPRA-affected retina. Expression of all RPGR splice variants increased later in the disease, when retinas were undergoing active degeneration. The results provide further evidence of cross-species retention of a complex splicing pattern in the 3' portion of RPGR, the functional significance of which is unknown. In addition, the possibility of another disease locus in the RP3 region is supported.

  7. IL-2R{gamma} gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease

    SciTech Connect

    Henthorn, P.S.; Fimiani, V.M.; Patterson, D.F.

    1994-09-01

    X-linked severe combined immunodeficiency (SCID) is characterized by profound defects in cellular and humoral immunity and, in humans, is associated with mutations in the gene for the {gamma} chain of the IL-2 receptor (IL-2R{gamma}). We have examined this gene in a colony of dogs established from a single X-linked SCID carrier female. Affected dogs have a 4-bp deletion in the first exon of the IL-2R{gamma} gene, which precludes the production of a functional protein, demonstrating that the canine disease is a true homologue of human X-linked SCID. 37 refs., 3 figs.

  8. Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy

    PubMed Central

    Ravin, Suk See Ting–De; Kennedy, Douglas R.; Naumann, Nora; Kennedy, Jeffrey S.; Choi, Uimook; Hartnett, Brian J.; Linton, Gilda F.; Whiting-Theobald, Narda L.; Moore, Peter F.; Vernau, William; Malech, Harry L.; Felsburg, Peter J.

    2006-01-01

    X-linked severe combined immunodeficiency (XSCID) is characterized by profound immunodeficiency and early mortality, the only potential cure being hematopoietic stem cell (HSC) transplantation or gene therapy. Current clinical gene therapy protocols targeting HSCs are based upon ex vivo gene transfer, potentially limited by the adequacy of HSC harvest, transduction efficiencies of repopulating HSCs, and the potential loss of their engraftment potential during ex vivo culture. We demonstrate an important proof of principle by showing achievement of durable immune reconstitution in XSCID dogs following intravenous injection of concentrated RD114-pseudotyped retrovirus vector encoding the corrective gene, the interleukin-2 receptor γ chain (γc). In 3 of 4 dogs treated, normalization of numbers and function of T cells were observed. Two long-term–surviving animals (16 and 18 months) showed significant marking of B lymphocytes and myeloid cells, normalization of IgG levels, and protective humoral immune response to immunization. There were no adverse effects from in vivo gene therapy, and in one dog that reached sexual maturity, sparing of gonadal tissue from gene transfer was demonstrated. This is the first demonstration that in vivo gene therapy targeting HSCs can restore both cellular and humoral immunity in a large-animal model of a fatal immunodeficiency. PMID:16384923

  9. Profiles of Steroid Hormones in Canine X-Linked Muscular Dystrophy via Stable Isotope Dilution LC-MS/MS.

    PubMed

    Martins-Júnior, Helio A; Simas, Rosineide C; Brolio, Marina P; Ferreira, Christina R; Perecin, Felipe; Nogueira, Guilherme de P; Miglino, Maria A; Martins, Daniele S; Eberlin, Marcos N; Ambrósio, Carlos E

    2015-01-01

    Golden retriever muscular dystrophy (GRMD) provides the best animal model for characterizing the disease progress of the human disorder, Duchenne muscular dystrophy (DMD). The purpose of this study was to determine steroid hormone concentration profiles in healthy golden retriever dogs (control group - CtGR) versus GRMD-gene carrier (CaGR) and affected female dogs (AfCR). Therefore, a sensitive and specific analytical method was developed and validated to determine the estradiol, progesterone, cortisol, and testosterone levels in the canine serum by isotope dilution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). To more accurately understand the dynamic nature of the serum steroid profile, the fluctuating levels of these four steroid hormones over the estrous cycle were compared across the three experimental groups using a multivariate statistical analysis. The concentration profiles of estradiol, cortisol, progesterone, and testosterone revealed a characteristic pattern for each studied group at each specific estrous phase. Additionally, several important changes in the serum concentrations of cortisol and estradiol in the CaGR and AfCR groups seem to be correlated with the status and progression of the muscular dystrophy. A comprehensive and quantitative monitoring of steroid profiles throughout the estrous cycle of normal and GRMD dogs were achieved. Significant differences in these profiles were observed between GRMD and healthy animals, most notably for estradiol. These findings contribute to a better understanding of both dog reproduction and the muscular dystrophy pathology. Our data open new venues for hormonal behavior studies in dystrophinopathies and that may affect the quality of life of DMD patients.

  10. Dystrophin deficiency in canine X-linked muscular dystrophy in Japan (CXMDJ) alters myosin heavy chain expression profiles in the diaphragm more markedly than in the tibialis cranialis muscle

    PubMed Central

    Yuasa, Katsutoshi; Nakamura, Akinori; Hijikata, Takao; Takeda, Shinichi

    2008-01-01

    Background Skeletal muscles are composed of heterogeneous collections of muscle fiber types, the arrangement of which contributes to a variety of functional capabilities in many muscle types. Furthermore, skeletal muscles can adapt individual myofibers under various circumstances, such as disease and exercise, by changing fiber types. This study was performed to examine the influence of dystrophin deficiency on fiber type composition of skeletal muscles in canine X-linked muscular dystrophy in Japan (CXMDJ), a large animal model for Duchenne muscular dystrophy. Methods We used tibialis cranialis (TC) muscles and diaphragms of normal dogs and those with CXMDJ at various ages from 1 month to 3 years old. For classification of fiber types, muscle sections were immunostained with antibodies against fast, slow, or developmental myosin heavy chain (MHC), and the number and size of these fibers were analyzed. In addition, MHC isoforms were detected by gel electrophoresis. Results In comparison with TC muscles of CXMDJ, the number of fibers expressing slow MHC increased markedly and the number of fibers expressing fast MHC decreased with growth in the affected diaphragm. In populations of muscle fibers expressing fast and/or slow MHC(s) but not developmental MHC of CXMDJ muscles, slow MHC fibers were predominant in number and showed selective enlargement. Especially, in CXMDJ diaphragms, the proportions of slow MHC fibers were significantly larger in populations of myofibers with non-expression of developmental MHC. Analyses of MHC isoforms also indicated a marked increase of type I and decrease of type IIA isoforms in the affected diaphragm at ages over 6 months. In addition, expression of developmental (embryonic and/or neonatal) MHC decreased in the CXMDJ diaphragm in adults, in contrast to continuous high-level expression in affected TC muscle. Conclusion The CXMDJ diaphragm showed marked changes in fiber type composition unlike TC muscles, suggesting that the affected

  11. X-linked congenital retinoschisis.

    PubMed

    Kellner, U; Brümmer, S; Foerster, M H; Wessing, A

    1990-01-01

    The natural history and electrophysiological findings of 52 patients with X-linked congenital retinoschisis with a follow-up of up to 26 years are described. The mean visual acuity was reduced to 0.24 +/- 0.2 and remained unchanged in most patients during this time. If visual loss occurred, it usually happened in the first decennium. The complications were retinal detachments in 11% and vitreous hemorrhages in 4% of the eyes. In general, the vitreous hemorrhages resolved spontaneously. Retinal detachments were treated successfully with conventional buckling procedures. Redetachments occurred in about 40%. Prophylactic laser coagulation was of no use because it was complicated by detachment in 43% of our series. The electro-oculogram was usually normal. In addition to the known electrorentinographic findings of normal a-wave and reduced b-wave amplitudes, we found prolonged b-wave latencies and implicit times, as well as a reduced 30 Hz flicker response.

  12. Seizures and X-linked intellectual disability

    PubMed Central

    Stevenson, Roger E.; Holden, Kenton R.; Rogers, R. Curtis; Schwartz, Charles E.

    2012-01-01

    Intellectual disability occurs as an isolated X-linked trait and as a component of recognizable X-linked syndromes in the company of somatic, metabolic, neuromuscular, or behavioral abnormalities. Seizures accompany intellectual disability in almost half of these X-linked disorders. The spectrum of seizures found in the X-linked intellectual disability syndromes is broad, varying in time of onset, type of seizure, and response to anticonvulsant therapy. The majority of the genes associated with XLID and seizures have now been identified. PMID:22377486

  13. Genetics Home Reference: X-linked sideroblastic anemia

    MedlinePlus

    ... Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description X-linked sideroblastic anemia is an inherited disorder that prevents developing red ...

  14. A Simulation of X-Linked Inheritance.

    ERIC Educational Resources Information Center

    Harrell, Pamela Esprivalo

    1997-01-01

    Describes how to lead students through a classroom-based simulation to teach a variety of concepts such as X-linked traits, sex determination, and sex anomalies. The simulation utilizes inexpensive materials such as plastic eggs that twist apart to represent human eggs and sperm. (AIM)

  15. Genetics Home Reference: X-linked adrenoleukodystrophy

    MedlinePlus

    ... 1016/j.bbadis.2012.03.012. Epub 2012 Mar 28. Review. Citation on PubMed Kemp S, Pujol A, ... X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007 Mar;3(3):140-51. Review. Citation on PubMed ...

  16. Therapy of X-linked adrenoleukodystrophy.

    PubMed

    Moser, Hugo W

    2006-04-01

    Current therapies for X-linked adrenoleukodystrophy (X-ALD) include replacement therapy with adrenal steroids, which is mandatory for all patients with impaired adrenal function but does not alter neurological progression significantly; dietary therapy with "Lorenzo's Oil," which appears to have a preventive effect in asymptomatic boys whose brain MRI is normal; and hematopoietic stem cell transplantation in patients in the early stage of the cerebral inflammatory phenotype. Application of these interventions requires careful assessment of the patients' phenotype, which often changes over time. Family screening provides important opportunities for disease prevention.

  17. Genetics Home Reference: X-linked sideroblastic anemia and ataxia

    MedlinePlus

    ... linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Enable Javascript to view the expand/ ... Open All Close All Description X-linked sideroblastic anemia and ataxia is a rare condition characterized by ...

  18. Genetics Home Reference: X-linked chondrodysplasia punctata 2

    MedlinePlus

    ... linked chondrodysplasia punctata 2 X-linked chondrodysplasia punctata 2 Enable Javascript to view the expand/collapse boxes. ... All Close All Description X-linked chondrodysplasia punctata 2 is a disorder characterized by bone, skin, and ...

  19. Genetics Home Reference: X-linked chondrodysplasia punctata 1

    MedlinePlus

    ... linked chondrodysplasia punctata 1 X-linked chondrodysplasia punctata 1 Enable Javascript to view the expand/collapse boxes. ... All Close All Description X-linked chondrodysplasia punctata 1 is a disorder of cartilage and bone development ...

  20. Genetics Home Reference: X-linked intellectual disability, Siderius type

    MedlinePlus

    ... linked intellectual disability, Siderius type X-linked intellectual disability, Siderius type Enable Javascript to view the expand/ ... Open All Close All Description X-linked intellectual disability, Siderius type is a condition characterized by mild ...

  1. Dietary management of X-linked adrenoleukodystrophy.

    PubMed

    Moser, H W; Borel, J

    1995-01-01

    Adrenoleukodystrophy (ALD) is an X-linked disorder that involves mainly the nervous system white matter and adrenal cortex. It is associated with the accumulation of saturated very-long-chain fatty acids (VLCFAs), such as hexacosanoic acid (C26:0), that occurs as a result of the impaired capacity to degrade these substances, a reaction that normally takes place in the peroxisome. The VLCFAs originate from the diet and are also synthesized endogenously. Interest in dietary therapy arose from the observation that the administration of oils containing erucic and oleic acid (Lorenzo's oil), when combined with restriction of dietary intake of VLCFAs, can normalize plasma VLCFA levels in ALD patients. Clinical results in patients who are already symptomatic have been disappointing. However, preliminary data, still in need of confirmation, suggest that dietary therapy begun in asymptomatic patients can reduce the frequency and severity of later neurological disability.

  2. X-linked cardiomyopathy is heterogeneous

    SciTech Connect

    Wilson, M.J.; Sillence, D.O.; Mulley, J.C.

    1994-09-01

    Two major loci of X-linked cardiomyopathy have been mapped by linkage analysis. The gene for X-linked dilated cardiomyopathy (XLCM) is mapped to the dystrophin locus at Xp21, while Barth syndrome has been localised to distal Xq28. XLCM usually presents in juvenile males with no skeletal disease but decreased dystrophin in cardiac muscle. Barth syndrome most often presents in infants and is characterized by skeletal myopathy, short stature and neutropenia in association with cardiomyopathy of variable severity. Prior to carrier or prenatal diagnosis in a family, delineation of the cardiomyopathy locus involved is essential. We report the linkage mapping of a large kindred in which several male infants have died with hypertrophic cardiomyopathy. There is a family history of unexplained death of infant males less than 6 months old over 4 generations. Features of Barth syndrome such as short stature, skeletal myopathy and neutropenia have not been observed. Genotyping at 10 marker loci in Xq28 has revealed significant pairwise lod scores with the cardiomyopathy phenotype at DXS52 (Z=2.21 at {theta}=0.0), at markers p26 and p39 near DXS15 (Z=2.30 at {theta}=0.0) and at F8C (Z=2.24 at {theta}=0.0). A recombinant detected with DXS296 defines the proximal limit to the localization. No recombinants were detected at any of the loci distal to DXS296. The most distal marker in Xq28, DXS1108, is within 500 kb of the telomere. As the gene in this family is localized to Xq28, it is possible that this disorder is an allelic variant at the Barth syndrome locus.

  3. Mutation detection in X-linked hydrocephalus

    SciTech Connect

    Forrest, S.M.; Balnaves, M.E.; Rosenthal, A.

    1994-09-01

    X-linked hydrocephalus (XLH), which maps to Xq28, affects about 1 in 30,000 male births. A candidate gene, L1-CAM, which codes for a neural adhesion molecule, mapped to the same region of the X chromosome. Rosenthal et al. (1992) identified a patient with XLH that had aberrant splicing of L1-CAM. A mutation at a potential branch point signal in an intron was identified. The gene has a number of exons and encodes a 4.2 kb mRNA. We isolated RNA from lymphocytes or fibroblasts from five XLH patients. cDNA was synthesized and the gene was amplified in two overlapping fragments, 2.2 kb and 1.7 kb respectively. A nested PCR approach with two rounds of PCR amplification was employed. Patient 900124 did not have a full length 5{prime} fragment and 880022 did not have a full length 3{prime} product. Restriction digestions defined the region of the alteration in the messenger RNA and sequencing in this region showed the loss of exons 10 and 21, respectively. All 5{prime} and 3{prime} products were also digested with several restriction enzymes (e.g., Msp I, Taq I), which have CG in their recognition sites, in the hope that point mutations that alter these restriction enzyme sites might be identified. A point mutation creating an Msp I site was found in patient 930067.

  4. [X-linked adrenoleukodystrophy--2 case reports].

    PubMed

    Dumić, M; Ille, J; Plavsić, V; Filipović-Grcić, B; Vrljicak, K; Barisić, N; Roscher, A

    1998-01-01

    Cases of a ten-year-old boy with childhood cerebral adrenoleukodystrophy (ALD) and a 22-year-old youngster with adrenomyeloneuropathy (AMN) are reported. ALD is an inherited, X-linked perixisomal disorder associated with the accumulation of very long chain fatty acids (VLCFA). Neurological symptoms occur due to progressive demyelination and destruction of cerebral white matter and primary adrenal insufficiency. The boy with ALD manifested neurological signs (impaired spatial orientation, visual disturbances, poor handwriting, seizures). Latent primary adrenal insufficiency was established, and successfully treated by gluco- and mineralocorticoids. Lorenzo's oil (mixture of glyceroltrioleate:glyceroltrierucate 4:1) treatment significantly reduced elevated concentrations of VLCFA, but in spite of that, neurological symptoms progressed and the boy died a year after the initial clinical presentation of the disease. The boy with AMN revealed primary adrenal insufficiency at the age of 15 years. AMN was suspected when hair and eyebrows loss occurred and the diagnosis was established due to elevated VLCFA levels in the serum at the age of 22 years. On examination no neurologic signs of the disease could be detected. Adrenal insufficiency is well controlled by gluco- and mineralocorticoids. In addition to the previously described two women who were symptomatic heterozygotes we now also report on two patients with ALD and AMN. The patients reported are the first four with this peroxisomal disorder described in Croatia so far. Probably a great number of such patients remains unrecognised. Therefore, it is necessary to measure the serum VLCFA levels in males with primary adrenal insufficiency, and in those with signs of progressive central demyelination and destruction of cerebral white matter accompanied by neurological symptoms of unknown etiology.

  5. Therapy of X-linked adrenoleukodystrophy.

    PubMed

    Semmler, Alexander; Köhler, Wolfgang; Jung, Hans H; Weller, Michael; Linnebank, Michael

    2008-09-01

    X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFAs). Primary manifestations occur in the CNS, the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. Phenotypes range from rapidly progressive cerebral disease with childhood (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [ACALD]) onset leading to death within a few years, over adult-onset adrenomyeloneuropathy (AMN) with or without focal CNS demyelination, AMN converting into a rapidly progressive, cerebral demyelinating phenotype resembling CCALD, to slow disease progression over decades, or adrenal insufficiency only. Approximately 50% of female heterozygotes develop moderate spastic paresis resembling the AMN phenotype. This review focuses on current experiences with different therapeutic approaches. Lorenzo's oil did not prove to be effective in cerebral inflammatory disease variants, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction. Hormone-replacement therapy is necessary in all patients with adrenal insufficiency. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD, and may well also be a final therapeutic option in early ACALD patients. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological upregulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovastatin are candidates

  6. Genetics Home Reference: X-linked lymphoproliferative disease

    MedlinePlus

    ... the development of specialized T cells called natural killer T cells. The SAP protein also helps control ... PubMed GeneReview: Lymphoproliferative Disease, X-Linked Latour S. Natural killer T cells and X-linked lymphoproliferative syndrome. Curr ...

  7. Genetics Home Reference: X-linked juvenile retinoschisis

    MedlinePlus

    ... to the retina impairs the sharpness of vision (visual acuity) in both eyes. Typically, X-linked juvenile ... in the same direction (strabismus) and farsightedness ( hyperopia ). Visual acuity often declines in childhood and adolescence but ...

  8. X inactivation and reactivation in X-linked diseases.

    PubMed

    Vacca, Marcella; Della Ragione, Floriana; Scalabrì, Francesco; D'Esposito, Maurizio

    2016-08-01

    X chromosome inactivation (XCI) is the phenomenon by which mammals compensate for dosage of X-linked genes in females (XX) versus males (XY). XCI patterns can be random or show extreme skewing, and can modify the mode of inheritance of X-driven phenotypes, which contributes to the variability of human pathologies. Recent findings have shown reversibility of the XCI process, which has opened new avenues in the approaches used for the treatment of X-linked diseases. PMID:26994527

  9. X chromosome inactivation and X-linked mental retardation

    SciTech Connect

    Willard, H.F. |

    1996-07-12

    The expression of X-linked genes in females heterozygous for X-linked defects can be modulated by epigenetic control mechanisms that constitute the X chromosome inactivation pathway. At least four different effects have been found to influence, in females, the phenotypic expression of genes responsible for X-linked mental retardation (XLMR). First, non-random X inactivation, due either to stochastic or genetic factors, can result in tissues in which one cell type (for example, that in which the X chromosome carrying a mutant XLMR gene is active) dominates, instead of the normal mosaic cell population expected as a result of random X inactivation. Second, skewed inactivation of the normal X in individuals carrying a deletion of part of the X chromosome has been documented in a number of mentally retarded females. Third, functional disomy of X-linked genes that are expressed inappropriately due to the absence of X inactivation has been found in mentally retarded females with structurally abnormal X chromosomes that do not contain the X inactivation center. And fourth, dose-dependent overexpression of X-linked genes that normally {open_quotes}escape{close_quotes} X inactivation may account for the mental and developmental delay associated with increasing numbers of otherwise inactive X chromosomes in individuals with X chromosome aneuploidy. 53 refs., 1 fig.

  10. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    PubMed

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

  11. X-linked dominant retinitis pigmentosa in an American family

    SciTech Connect

    McGuire, R.E.; Daiger, S.P.; Blanton, S.H.

    1994-09-01

    Retinitis pigmentosa is a genetically heterogeneous disease with autosomal dominant (adRP), autosomal recessive and X-linked forms. At least 3 forms of X-linked retinitis pigmentosa have been reported: RP2 which maps to Xp11.4-p 11.23, RP3 which maps to Xp21.1 and RP6, which maps to Xp21.3-p21.1. The X-linked forms of retinitis pigmentosa are generally considered to be recessive as female carriers are not affected or are much less affected than males. Here we report a five generation American family with X-linked retinitis pigmentosa in which both males and females are significantly affected. The disease locus in this family appears to be distinct from RP2 and RP3. The American family (UTAD054) presents with early-onset retinitis pigmentosa. The family appeared to fit an autosomal dominant pattern; however, linkage testing excluded all known adRP loci. Absence of male-to-male transmission in the pedigree suggested the possibility of X-linked dominant inheritance. Thus we tested six microsatellite markers that map to Xp (DXS987, DXS989, DXS993, DXS999, DXS1003 and DXS1110). Of these, DXS989 showed tight linkage with one allele (199) showing a 100% concordance with disease status. The odds favoring an X-linked dominant mode of inheritance in this family, versus autosomal dominant, are 10{sup 5}:1. In addition, recombinations for DXS999, and dXS1110, the two markers flanking DXS989, were observed in affected individuals. These data map the disease locus in this family to a 9 mb region on the X chromosome between Xp22.11 and Xp21.41. In addition, the recombinant individuals exclude close linkage to RP2 and RP3. The observance of high penetrance in females indicates that this family has X-linked dominant retinitis pigmentosa. We suggest that this mode of inheritance should be considered in other families with dominant retinitis pigmentosa but an absence of male-to-male transmission.

  12. Canine Distemper

    MedlinePlus

    Although this brochure provides basic information about canine distemper, your veterinarian is always your best source of health information. Consult your veterinarian for more information about canine distemper and its prevention. ...

  13. Neurological involvement in X-linked hypophosphataemic rickets.

    PubMed

    Bradbury, P G; Brenton, D P; Stern, G M

    1987-06-01

    X-linked hypophosphataemic rickets is a familial form of Vitamin D resistant rickets in which gross bony and ligamentous changes may occur. Two patients showing severe spinal disease with evidence of spinal cord compression requiring neurosurgical intervention are reported. The management of such lesions may be problematic as cord compression may be found at several levels at presentation, and further difficulties develop after neurosurgical treatment.

  14. Evolving practice: X-linked agammaglobulinemia and lung transplantation.

    PubMed

    Barnes, S; Kotecha, S; Douglass, J A; Paul, E; Hore-Lacey, F; Stirling, R; Snell, G I; Westall, G P

    2015-04-01

    X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD). PMID:25736826

  15. Prenatal diagnosis of X-linked recessive Lenz microphthalmia syndrome.

    PubMed

    Suzumori, Nobuhiro; Kaname, Tadashi; Muramatsu, Yukako; Yanagi, Kumiko; Kumagai, Kyoko; Mizuno, Seiji; Naritomi, Kenji; Saitoh, Shinji; Sugiura-Ogasawara, Mayumi

    2013-11-01

    Lenz microphthalmia syndrome comprises microphthalmia-anophthalmia with mental retardation, malformed ears and skeletal anomalies, and is inherited in an X-linked recessive pattern. In 2004, it was reported that the missense mutation (BCL-6 co-repressor gene [BCOR] c.254C>T, p.P85L) in a single family with Lenz microphthalmia syndrome co-segregated with the disease phenotype. We report a case of prenatal diagnosis for X-linked recessive Lenz microphthalmia syndrome with the mutation. A 32-year-old gravida 5, para 2 Japanese woman was referred to Nagoya City University Hospital at 15 weeks of gestation. After genetic counseling and informed consent, amniocentesis was performed for fetal karyotyping, which was 46,XY. Using the extracted DNA from cultured amniotic cells, fetal search for BCOR c.254C>T mutation was undertaken. The couple requested medical termination of pregnancy, and the postabortion examination confirmed the diagnosis. This is the third report of a BCOR mutation, associated with X-linked syndromic microphthalmia, and most importantly, it is always the same mutation. The prenatal genetic diagnosis of the Lenz microphthalmia syndrome allowed time for parental counseling and delivery planning.

  16. Prenatal diagnosis of X-linked recessive Lenz microphthalmia syndrome.

    PubMed

    Suzumori, Nobuhiro; Kaname, Tadashi; Muramatsu, Yukako; Yanagi, Kumiko; Kumagai, Kyoko; Mizuno, Seiji; Naritomi, Kenji; Saitoh, Shinji; Sugiura-Ogasawara, Mayumi

    2013-11-01

    Lenz microphthalmia syndrome comprises microphthalmia-anophthalmia with mental retardation, malformed ears and skeletal anomalies, and is inherited in an X-linked recessive pattern. In 2004, it was reported that the missense mutation (BCL-6 co-repressor gene [BCOR] c.254C>T, p.P85L) in a single family with Lenz microphthalmia syndrome co-segregated with the disease phenotype. We report a case of prenatal diagnosis for X-linked recessive Lenz microphthalmia syndrome with the mutation. A 32-year-old gravida 5, para 2 Japanese woman was referred to Nagoya City University Hospital at 15 weeks of gestation. After genetic counseling and informed consent, amniocentesis was performed for fetal karyotyping, which was 46,XY. Using the extracted DNA from cultured amniotic cells, fetal search for BCOR c.254C>T mutation was undertaken. The couple requested medical termination of pregnancy, and the postabortion examination confirmed the diagnosis. This is the third report of a BCOR mutation, associated with X-linked syndromic microphthalmia, and most importantly, it is always the same mutation. The prenatal genetic diagnosis of the Lenz microphthalmia syndrome allowed time for parental counseling and delivery planning. PMID:23815237

  17. NADPH oxidase deficiency in X-linked chronic granulomatous disease.

    PubMed Central

    Hohn, D C; Lehrer, R I

    1975-01-01

    We measured the cyanide-insensitive pyridine nucleotide oxidase activity of fractionated resting and phagocytic neutrophils from 11 normal donors, 1 patient with hereditary deficiency of myeloperoxidase, and 7 patients with X-linked chronic granulomatous disease (CGD). When measured under optimal conditions (at pH 5.5 and in the presence of 0.5 mM Mn++), NADPH oxidase activity increased fourfold with phagocytosis and was six-fold higher than with NADH. Phagocytic neutrophils from patients with CGD were markedly deficient in NADPH oxidase activity. Images PMID:235560

  18. Frontometaphyseal dysplasia: autosomal dominant or X-linked?

    PubMed Central

    Beighton, P; Hamersma, H

    1980-01-01

    The clinical and radiographic manifestations in a 45-year-old male with frontometaphyseal dysplasia (FMD) are documented and depicted. Deafness and degenerative osteoarthropathy in weight-bearing joints were the main clinical problems. Widespread patchy cranial sclerosis was reminiscent of Paget's disease, while digital deformity resembled rheumatoid arthritis. On the basis of a review and tabulation of published reports, evidence emerges to support the concept of X-linked inheritance. The relationship between FMD and osteodysplasty remains a matter for speculation. Images PMID:7189217

  19. Genetics Home Reference: alpha thalassemia X-linked intellectual disability syndrome

    MedlinePlus

    ... intellectual disability syndrome alpha thalassemia X-linked intellectual disability syndrome Enable Javascript to view the expand/collapse ... Close All Description Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder that affects many ...

  20. Infantile Growth Hormone Deficiency and X- Linked Adrenal Hypoplasia Congenita

    PubMed Central

    Chung, Stephanie T.; Chi, Carolyn H.; Haymond, Morey W.; Jeha, George S.

    2015-01-01

    Context X-linked adrenal hypoplasia congenita (AHC) is a rare but important cause of primary adrenal insufficiency and can be associated with significant morbidity and mortality. AHC is caused by mutations within the NROB1 gene that codes for the DAX-1 protein, an orphan nuclear receptor essential for the development of the hypothalamic-pituitary-adrenal axis. Affected individuals typically present in early infancy with adrenal insufficiency and growth is usually normal once medical therapy is instituted. Here we report the first case of growth hormone deficiency in an infant with AHC and a novel NROB1 missense mutation. Case A two-week old infant presented with salt-losing adrenal crises and a normal newborn screen. Tests of adrenal function confirmed adrenal hypoplasia congenita and molecular evaluation revealed a novel missense NROB1 mutation. Replacement steroid therapy was promptly initiated, but he subsequently developed growth failure despite optimal nutritional and medical steroid therapy. Further biochemical analyses confirmed isolated idiopathic growth hormone deficiency. Conclusions Growth failure in adequately treated infants with adrenal hypoplasia congenita is rare and the role of DAX-1 in the development of pituitary somatotropes is not known. There is variable genotype-phenotype correlation in X-linked adrenal hypoplasia congenita but novel NROB1 missense mutations could offer insight into the function of the various DAX-1 ligand-binding domains. PMID:27110597

  1. X-linked recessive atrophic macular degeneration from RPGR mutation.

    PubMed

    Ayyagari, Radha; Demirci, F Yesim; Liu, Jiafan; Bingham, Eve L; Stringham, Heather; Kakuk, Laura E; Boehnke, Michael; Gorin, Michael B; Richards, Julia E; Sieving, Paul A

    2002-08-01

    We mapped a new X-linked recessive atrophic macular degeneration locus to Xp21.1-p11.4 and show allelic involvement of the gene RPGR, which normally causes severe peripheral retinal degeneration leading to global blindness. Ten affected males whom we examined had primarily macular atrophy causing progressive loss of visual acuity with minimal peripheral visual impairment. One additional male showed extensive macular degeneration plus peripheral loss of retinal pigment epithelium and choriocapillaries. Full-field electroretinograms (ERGs) showed normal cone and rod responses in some affected males despite advanced macular degeneration, emphasizing the dissociation of atrophic macular degeneration from generalized cone degenerations, including X-linked cone dystrophy (COD1). The RPGR gene nonsense mutation G-->T at open reading frame (ORF)15+1164 cosegregated with the disease and may create a donor splice site. Identification of an RPGR mutation in atrophic maculardegeneration expands the phenotypic range associated with this gene and provides a new tool for the dissection of the relationship between clinically different retinal pathologies.

  2. Severe Papillomavirus Infection Progressing to Metastatic Squamous Cell Carcinoma in Bone Marrow-Transplanted X-Linked SCID Dogs

    PubMed Central

    Goldschmidt, Michael H.; Kennedy, Jeffrey S.; Kennedy, Douglas R.; Yuan, Hang; Holt, David E.; Casal, Margret L.; Traas, Anne M.; Mauldin, Elizabeth A.; Moore, Peter F.; Henthorn, Paula S.; Hartnett, Brian J.; Weinberg, Kenneth I.; Schlegel, Richard; Felsburg, Peter J.

    2006-01-01

    Canine X-linked severe combined immunodeficiency (XSCID) is due to mutations in the common gamma chain (γc) gene and is identical clinically and immunologically to human XSCID, making it a true homologue of the human disease. Bone marrow-transplanted (BMT) XSCID dogs not only engraft donor T cells and reconstitute normal T-cell function but, in contrast to the majority of transplanted human XSCID patients, also engraft donor B cells and reconstitute normal humoral immune function. Shortly after our initial report of successful BMT of XSCID dogs, it soon became evident that transplanted XSCID dogs developed late-onset severe chronic cutaneous infections containing a newly described canine papillomavirus. This is analogous to the late-onset cutaneous papillomavirus infection recently described for human XSCID patients following BMT. Of 24 transplanted XSCID dogs followed for at least 1 year post-BMT, 71% developed chronic canine papillomavirus infection. Six of the transplanted dogs that developed cutaneous papillomas were maintained for >3 1/2 years post-BMT for use as breeders. Four of these six dogs (67%) developed invasive squamous cell carcinoma (SCC), with three of the dogs (75%) eventually developing metastatic SCC, an extremely rare consequence of SCC in the dog. This finding raises the question of whether SCC will develop in transplanted human XSCID patients later in life. Canine XSCID therefore provides an ideal animal model with which to study the role of the γc-dependent signaling pathway in the response to papillomavirus infections and the progression of these viral infections to metastatic SCC. PMID:16775349

  3. No cardiomyopathy in X-linked myopathy with excessive autophagy.

    PubMed

    Saraste, Antti; Koskenvuo, Juha W; Airaksinen, Juhani; Ramachandran, Nivetha; Munteanu, Iulia; Udd, Bjarne; Huovinen, Sanna; Kalimo, Hannu; Minassian, Berge A

    2015-06-01

    In X-linked myopathy with excessive autophagy (XMEA) progressive sarcoplasmic accumulation of autolysosomes filled with undegraded debris leads to atrophy and weakness of skeletal muscles. XMEA is caused by compromised acidification of lysosomes resulting from hypofunction of the proton pump vacuolar ATPase (V-ATPase), due to hypomorphic mutations in VMA21, whose protein product assembles V-ATPase. To what extent the cardiac muscle is affected is unknown. Therefore we performed a comprehensive cardiac evaluation in four male XMEA patients, and also examined pathology of one deceased patient's cardiac and skeletal muscle. None of the symptomatic men (aged 25-48 years) had history or symptoms of cardiomyopathy. Resting electrocardiograms and echocardiographies were normal. MRI showed normal left ventricle ejection fraction and myocardial mass. Myocardial late-gadolinium enhancement was not detected. The deceased patient's skeletal but not cardiac muscle showed characteristic accumulation of autophagic vacuoles. In conclusion, in classic XMEA the myocardium is structurally, electrically and clinically spared.

  4. X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy

    PubMed Central

    van Geel, B. M; Assies, J.; Wanders, R.; Barth, P.

    1997-01-01

    X linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal metabolism, biochemically characterised by accumulation of saturated very long chain fatty acids. Accumulation of these fatty acids is associated with cerebral demyelination, peripheral nerve abnormalities, and adrenocortical and testicular insufficiency. The lowest estimated birth incidence is one per 100 000. At least six phenotypes can be distinguished, of which the two most frequent are childhood cerebral ALD and adrenomyeloneuropathy. The X-ALD gene has been identified, but thus far no relation between genotype and phenotype has been found. Diagnosis is relatively easy and can be confirmed reliably, and prenatal testing is possible in affected families. Several therapeutic options, some with promising perspectives, are available. Neurologists and other physicians seem not to be familiar with the many facets of X-ALD. In this review, the clinical presentation, the relative frequencies of the different phenotypes, and the diagnostic and therapeutic options are presented.

 PMID:9221959

  5. X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy.

    PubMed

    Nakamura, Akinori

    2015-01-01

    X-linked dilated cardiomyopathy (XLDCM) is a distinct phenotype of dystrophinopathy characterized by preferential cardiac involvement without any overt skeletal myopathy. XLDCM is caused by mutations of the Duchenne muscular dystrophy (DMD) gene and results in lethal heart failure in individuals between 10 and 20 years. Patients with Becker muscular dystrophy, an allelic disorder, have a milder phenotype of skeletal muscle involvement compared to Duchenne muscular dystrophy (DMD) and sometimes present with dilated cardiomyopathy. The precise relationship between mutations in the DMD gene and cardiomyopathy remain unclear. However, some hypothetical mechanisms are being considered to be associated with the presence of some several dystrophin isoforms, certain reported mutations, and an unknown dystrophin-related pathophysiological mechanism. Recent therapy for Duchenne muscular dystrophy, the severe dystrophinopathy phenotype, appears promising, but the presence of XLDCM highlights the importance of focusing on cardiomyopathy while elucidating the pathomechanism and developing treatment.

  6. [Dermatomyositis-like syndrome in x-linked agammaglobulinemia].

    PubMed

    Carvalho, P D; Costa, C; Rodrigues, M; Salvador, M J; Pereira da Silva, J A; Malcata, A

    2016-01-01

    Primary immunodeficiencies (PIDs) encompass more than 250 different pathological conditions. X-linked agammaglobulinemia (XLA) has been occasionally associated with cutaneous and muscular manifestations resembling dermatomyositis, often termed dermatomyositis-like syndrome (DLS). This syndrome has been associated with cutaneous, muscular and central nervous system manifestations, accompanying a persistent infection by an Echovirus. According to sixteen previously reported cases, this syndrome has a poor prognosis. We report the case of a 27-years old male, with XLA and DLS, successfully treated with 6 cycles of human immunoglobulin and methotrexate. Clinical symptoms improved dramatically with a complete resolution of the musculoskeletal manifestations. Despite this clinical response, prognosis should remain reserved. The evolution of this syndrome remains unpredictable and therapeutic options are limited. To the best of our knowledge, there are only a few reports of similar cases which have survived so many months after the diagnosis. PMID:27115112

  7. Recent developments in certain X-linked genetic eye disorders.

    PubMed

    Shastry, B S

    1993-09-01

    Over the past few years, genetic diseases of the ocular system have become very active and fast-growing research areas in the vision field. The rapid development of the recombinant DNA techniques together with somatic cell genetics, during the last two decades has fueled this progress. As a result, many genetic disease genes have been localized in the human chromosome and several of them have been isolated and characterized. These and other studies have profoundly enriched our basic understanding of genetic eye disorders. Although gene replacement therapy, prenatal diagnosis and carrier detection have not been extensively tried for genetic eye diseases, such attempts will now be feasible. Molecular analyses made it clear that there are many challenging problems that need attention. This report highlights some of these initial developments, particularly on the X-linked major genetic eye diseases. In order to help the beginners and general audience, a brief description of the clinical pathology and the molecular probes used to locate the genetic defects of certain disorders are presented. Disorders are arranged according to their linkage from telomere to telomere on the chromosome to give a coherent structure. It is hoped that this information is useful and of general interest for the beginners, established investigators and ophthalmologists.

  8. X-linked liver glycogenosis: From patient to gene

    SciTech Connect

    Willems, P.J.; Hendrickx, J.

    1994-09-01

    X-linked liver glycogenosis (XLG) is the most frequent glycogen storage disorder. Studying a collection of more than 50 XLG families, we have subdivided XLG into XLG I which shows a clear deficiency of phosphorylase kinase (PHK), and XLG II in which no enzyme deficiency has yet been found. However, the clinical pictures of XLG I and XLG II with hepatormegaly and growth retardation are indistinguishable. We have localized the XLG I and the XLG II gene by linkage analysis in multiple large families to the same chromosomal region in Xp22. Multipoint linkage analysis gave lod scores of above 15 in XLG I and above 4.5 in XLG II with Xp22 markers, whereas analysis of key recombinants located both disease genes between DXS143 and DXS989. Therefore, XLG I and XLG II might be due to allelic mutations in the same gene. To clone the disease gene, we searched for PHK subunit genes and isolated genomic and cDNA clones from a liver alpha subunit gene (PHKA2). As PHKA2 could be mapped by FISH and radiation hybrids to Xp22, it is a candidate gene for XLG. To prove that PHKA2 harbours the mutations responsible for XLG I and XLG II, we studied different XLG I and XLG II patients with Southern blot analysis and genomic SSCP scanning. Several mutations (nonsense mutations, splice site mutations) were identified indicating that PHKA2 is the XLG gene.

  9. Clinical Manifest X-Linked Recessive Adrenoleukodystrophy in a Female

    PubMed Central

    Jack, Gyda Hlin Skuladottir; Frederiksen, Anja; Andersen, Marianne

    2013-01-01

    Adrenoleukodystrophy (ALD) is a rare X-linked inherited leukodystrophy with a reduced capacity for degradation of very long chain fatty acids (VLCFAs). The intracellular accumulation of VLCFA leads to demyelination in the central nervous system (CNS) and cell destruction in the adrenal glands. ALD primarily affects males; however, females may develop milder symptoms that may be difficult to recognize. The present report describes a 35-year-old female who experienced a feeling of heaviness in the upper and lower limbs, pain in both knees, and difficulty climbing stairs, running, and jumping. Clinical examination revealed decreased sensitivity in the feet, particularly to touch. Deep tendon reflexes in the lower limbs were brisk, and Babinski's sign was present bilaterally. Multiple sclerosis (MS) was excluded, and all clinical and biochemical tests were normal. After two years of progressing symptoms, the patient was reevaluated and plasma levels of VLCFA were found to be elevated. Seven years prior to this finding, the patient had been found to be heterozygous for the missense mutation c.1679C> T, p.Pro560Leu on the ABCD1 gene (ATP-Binding Cassette subfamily D1). In conclusion, the patient's symptoms could be attributed to ALD. The present case underlines the importance of reevaluating family history in women presenting with vague neurological symptoms. PMID:23864971

  10. X-linked adrenoleukodystrophy presenting as Addison’s disease

    PubMed Central

    Morell, Bernhard Kaspar; Teichler, Jens; Budak, Kemal; Vollenweider, Jörg; Pavlicek, Vojtech

    2010-01-01

    We report the case of a young man with a history of attention deficit/hyperactivity disorder and mild cognitive impairment who presented with chronic fatigue, anorexia and progressive darkening of the skin. On laboratory testing, severely depressed concentrations of morning cortisol, along with highly elevated values of adrenocorticotropic hormone (ACTH) revealed primary adrenal insufficiency as the primary cause of the patient’s symptomatology. Imaging of the brain showed altered signal intensities in the parieto-occipital regions of the brain. The demonstration of increased very long chain fatty acids (VLCFA) established the diagnosis of adolescent X-linked adrenoleukodystrophy (X-ALD). Presenting at an advanced yet slowly progressive stage the patient was not a suitable candidate for haematopoietic stem cell transplantation (HSCT), and treatment focused on hormone replacement therapy, family counselling and supportive care. On follow-up visits within the following year, fatigue had diminished and there was no evidence of progressive neurological deficits. However, exacerbation of the psychiatric symptomatology resulted in admittance to a psychiatric ward. PMID:22753300

  11. Reduced X-linked nucleotide polymorphism in Drosophila simulans.

    PubMed

    Begun, D J; Whitley, P

    2000-05-23

    Population genetic theory predicts that selectively driven changes of allele frequency for both beneficial and deleterious mutants reduce polymorphism at tightly linked sites. All else being equal, these reductions in polymorphism are expected to be greater when recombination rates are lower. Therefore, the empirical observation of a positive correlation between recombination rates and amounts of DNA polymorphism across the Drosophila melanogaster genome can be explained by two very different types of natural selection. Here, we evaluate alternative models of effects of selection on linked sites by comparison of X-linked and autosomal variation. We present polymorphism data from 40 genes distributed across chromosome arms X and 3R of Drosophila simulans, a sibling species of D. melanogaster. We find significantly less silent polymorphism in D. simulans on the X chromosome than on 3R, but no difference between arms for silent divergence between species. This pattern is incompatible with predictions from theoretical studies on the effect of negative selection on linked sites. We propose that some form of positive selection having greater effects on sex chromosomes than on autosomes is the better explanation for the D. simulans data.

  12. Modeling X-Linked Ancestral Origins in Multiparental Populations

    PubMed Central

    Zheng, Chaozhi

    2015-01-01

    The models for the mosaic structure of an individual’s genome from multiparental populations have been developed primarily for autosomes, whereas X chromosomes receive very little attention. In this paper, we extend our previous approach to model ancestral origin processes along two X chromosomes in a mapping population, which is necessary for developing hidden Markov models in the reconstruction of ancestry blocks for X-linked quantitative trait locus mapping. The model accounts for the joint recombination pattern, the asymmetry between maternally and paternally derived X chromosomes, and the finiteness of population size. The model can be applied to various mapping populations such as the advanced intercross lines (AIL), the Collaborative Cross (CC), the heterogeneous stock (HS), the Diversity Outcross (DO), and the Drosophila synthetic population resource (DSPR). We further derive the map expansion, density (per Morgan) of recombination breakpoints, in advanced intercross populations with L inbred founders under the limit of an infinitely large population size. The analytic results show that for X chromosomes the genetic map expands linearly at a rate (per generation) of two-thirds times 1 – 10/(9L) for the AIL, and at a rate of two-thirds times 1 – 1/L for the DO and the HS, whereas for autosomes the map expands at a rate of 1 – 1/L for the AIL, the DO, and the HS. PMID:25740936

  13. Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

    PubMed Central

    Cowling, Belinda S.; Chevremont, Thierry; Prokic, Ivana; Kretz, Christine; Ferry, Arnaud; Coirault, Catherine; Koutsopoulos, Olga; Laugel, Vincent; Romero, Norma B.; Laporte, Jocelyn

    2014-01-01

    Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypotonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1–/y). Generation of Mtm1–/y mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle–specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients. PMID:24569376

  14. X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

    PubMed

    Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H; Bours, Vincent; Liu, Pengfei; W de Herder, Wouter; Pellegata, Natalia; Lupski, James R; Daly, Adrian F; Stratakis, Constantine A

    2015-06-01

    X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

  15. X-linked inheritance in neuronal migration disorders (NMD)

    SciTech Connect

    Andermann, E.; Dubeau, F.; Tampieri, D.

    1994-09-01

    With the advent of MRI imaging, an increasing number of NMD have been identified in patients with epilepsy. Although most cases have been sporadic, families with these disorders have now been reported in several types of NMD. Furthermore, subcortical bank heterotopia (SBH) or {open_quotes}double cortex syndrome{close_quotes} and periventricular nodular heterotopia (PNH) have a marked female predominance. Two females with SBH, mild mental retardation and seizures had sons with lissencephaly, severe retardation and seizures, and daughters with SBH. X-linked lissencephaly has been observed in several other families, and one girl with lissencephaly was found to have a de novo X-autosomal translocation with a breakpoint in chromosome Xq22. We have studied three families with two or more generations affected by PNH in females, a high frequency of spontaneous abortions and abnormal sex ratios in sibships. The clinical manifestations include seizures and normal intelligence. Three other families with PNH in females have been reported in the literature. Bilateral perisylvian polymicrogyria has been reported in monozygotic twins and in siblings, and we have studied a brother and sister with an affected maternal uncle. These findings suggest sex-linked dominant inheritance with male lethality or severe expression in males. The three disorders described above may represent different mutations of a single gene or mutations in two or more genes on the X-chromosome. At least one gene is probably located in chromosome band Xq22. Genetic linkage studies in families with NMD as well as a search for candidate genes such as adhesion molecules known to map on the X-chromosome should lead to the identification of the gene(s) responsible for these disorders.

  16. X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

    PubMed

    Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H; Bours, Vincent; Liu, Pengfei; W de Herder, Wouter; Pellegata, Natalia; Lupski, James R; Daly, Adrian F; Stratakis, Constantine A

    2015-06-01

    X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID:25712922

  17. Canine papillomaviruses.

    PubMed

    Lange, Christian E; Favrot, Claude

    2011-11-01

    Papillomaviruses can infect epithelia and induce proliferative disorders. Different types of canine papillomaviruses have been found to be associated with distinct pathologies including exophytic warts as in canine oral papillomatosis, endophytic warts, and pigmented plaques and, in some cases, squamous cell carcinomas. Virus infection is followed by a phase of subclinical infection before the onset of symptoms. A diagnosis can in some cases be made clinically but should be verified if there are any doubts. Most papillomas do regress spontaneously within a few months. Preventative vaccination is possible but not on the market.

  18. FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

    PubMed

    Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H; Silverman, Edwin K; Park, Taesung; Won, Sungho

    2016-09-01

    Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods.

  19. Canine Parvovirus

    MedlinePlus

    Finally, do not let your puppy or adult dog to come into contact with the fecal waste of other dogs while walking or playing outdoors. Prompt and proper ... advisable as a way to limit spread of canine parvovirus infection as well as other diseases that ...

  20. Canine neoplasia

    PubMed Central

    Prier, J. E.; Brodey, R. S.

    1963-01-01

    The authors review current knowledge of spontaneous neoplasms in the dog. The prevalence of certain types of canine tumour has been studied, and comparisons have been made with the occurrence of similar neoplasms in man. Where there are appropriate analogies between the two species, the dog with spontaneous tumours can be used for studies that are not practicable in man. Nutritional and morphological studies have been done on cells cultured from canine tumours. Some consistency has been demonstrated in the morphology of cultures of different tumours of the same type. Nutritional studies with the transmissible venereal sarcoma of the dog have shown the cells to be subject to a growth-repressing effect by SH-containing amino-acids. Attempts to transmit tumours to other dogs or other species have generally been unsuccessful. A transplantable tumour developed in a mouse injected with non-cellular material from a canine thyroid carcinoma, but it is not certain that the tumour was induced. Cell-culture studies have shown that some tumours yield a factor that is cytopathogenic for normal cells, but none has been shown capable of inducing neoplasms in vivo. ImagesFIG. 3FIG. 4FIG. 5FIG. 1FIG. 2FIG. 6 PMID:14058226

  1. Genetic hetergoeneity in X-linked hydrocephalus: Linkage to markers within Xq27. 3

    SciTech Connect

    Strain, L.; Brock, D.J.H.; Bonthron, D.T. ); Gosden, C.M. )

    1994-02-01

    X-linked hydrocephalus is a well-defined disorder which accounts for [ge]70% of hydrocephalus in males. Pathologically, the conditions is characterized by stenosis or obliteration of the aqueduct of Sylvius. Previous genetic linkage studies have suggested likelihood of genetic homogeneity for this condition, with close linkage to the DXS52 and F8C markers in Xq28. The authors have investigated a family with typical X-linked aqueductal stenosis, in which no linkage to these markers was present. In this family, close linkage was established to the DXS548 and FRAXA loci in Xq27.3. The findings demonstrate that X-linked aqueductal stenosis may result from mutations at two different loci on the X chromosome. Caution is indicated in using linkage for the prenatal diagnosis of X-linked hydrocephalus. 43 refs., 2 figs., 2 tabs.

  2. Refinement of the localization of the X-linked ocular albinism gene

    SciTech Connect

    Bergen, A.A.B.; Zijp, P.; Schuurman, E.J.M.; Bleeker-Wagemakers, E.M.; Apkarian, P. ); Ommen, G.J.B. van )

    1993-04-01

    Although physical and genetic mapping studies assigned the X-linked ocular albinism gene to Xp22.3, the exact gene order in this region is still unclear. The authors present additional genetic mapping data concerning X-linked ocular albinism that suggests the consensus order Xpter-STS-DXS237-KAL-(OA1, DXS143)- DXS85-DXS16-Xcen. 14 refs., 1 fig.

  3. Drosophila X-Linked Genes Have Lower Translation Rates than Autosomal Genes.

    PubMed

    Zhang, Zhenguo; Presgraves, Daven C

    2016-02-01

    In Drosophila, X-linked and autosomal genes achieve comparable expression at the mRNA level. Whether comparable X-autosome gene expression is realized at the translational and, ultimately, the protein levels is, however, unknown. Previous studies suggest the possibility of higher translation rates for X-linked genes owing to stronger usage of preferred codons. In this study, we use public ribosome profiling data from Drosophila melanogaster to infer translation rates on the X chromosome versus the autosomes. We find that X-linked genes have consistently lower ribosome densities than autosomal genes in S2 cells, early embryos, eggs, and mature oocytes. Surprisingly, the lower ribosome densities of X-linked genes are not consistent with faster translation elongation but instead imply slower translation initiation. In particular, X-linked genes have sequence features known to slow translation initiation such as stronger mRNA structure near start codons and longer 5'-UTRs. Comparison to outgroup species suggests that stronger mRNA structure is an evolved feature of Drosophila X chromosomes. Finally, we find that the magnitude of the X-autosome difference in ribosome densities is smaller for genes encoding members of protein complexes, suggesting that stoichiometry constrains the evolution of translation rates. In sum, our analyses suggest that Drosophila X-linked genes have evolved lower translation rates than autosomal genes despite stronger usage of preferred codons.

  4. Drosophila X-Linked Genes Have Lower Translation Rates than Autosomal Genes.

    PubMed

    Zhang, Zhenguo; Presgraves, Daven C

    2016-02-01

    In Drosophila, X-linked and autosomal genes achieve comparable expression at the mRNA level. Whether comparable X-autosome gene expression is realized at the translational and, ultimately, the protein levels is, however, unknown. Previous studies suggest the possibility of higher translation rates for X-linked genes owing to stronger usage of preferred codons. In this study, we use public ribosome profiling data from Drosophila melanogaster to infer translation rates on the X chromosome versus the autosomes. We find that X-linked genes have consistently lower ribosome densities than autosomal genes in S2 cells, early embryos, eggs, and mature oocytes. Surprisingly, the lower ribosome densities of X-linked genes are not consistent with faster translation elongation but instead imply slower translation initiation. In particular, X-linked genes have sequence features known to slow translation initiation such as stronger mRNA structure near start codons and longer 5'-UTRs. Comparison to outgroup species suggests that stronger mRNA structure is an evolved feature of Drosophila X chromosomes. Finally, we find that the magnitude of the X-autosome difference in ribosome densities is smaller for genes encoding members of protein complexes, suggesting that stoichiometry constrains the evolution of translation rates. In sum, our analyses suggest that Drosophila X-linked genes have evolved lower translation rates than autosomal genes despite stronger usage of preferred codons. PMID:26486873

  5. Canine lymphoma

    SciTech Connect

    Weller, R.E.

    1986-10-01

    Canine lymphoma has served as the ''workhorse'' for the development of veterinary oncology and as an important animal model for human non-Hodgkins lymphomas. Significant advances have been achieved in understanding the biological behavior of the disease and in its treatment. Although it is unlikely that a cure for lymphoma will be achieved, owners should be encouraged to treat their pets, provided they understand that only prolonged remissions and survivals are likely to result. Cooperative studies, employing large numbers of dogs, are needed to optimize and refine the classification scheme to provide a system with diagnostic and prognostic correlates and derive maximum benefit from therapeutic regimens. Such studies need to be prospective in nature, with a solid statistical base incorporated into their design. Rather than being content with what we have accomplished to date in treatment of canine lymphoma, the opportunity exists for the veterinary profession to make further significant contributions to the understanding and treatment of lymphoma in the dog. 10 refs., 4 tabs.

  6. Molecular characterization of co-occurring Duchenne muscular dystrophy and X-linked oculo-facio-cardio-dental syndrome in a girl.

    PubMed

    Jiang, Yong-hui; Fang, Ping; Adesina, Adekunle M; Furman, Patricia; Johnston, Jennifer J; Biesecker, Leslie G; Brown, Chester W

    2009-06-01

    Duchenne muscular dystrophy is an X-linked condition at the severe end of the spectrum of dystrophinopathies. Females with dystrophin mutations are at risk for cardiomyopathy, but are usually asymptomatic during childhood. However, some girls can exhibit features of Duchenne muscular dystrophy because of skewed X-inactivation, aneuploidy, or chromosomal rearrangement. Oculo-facio-cardio-dental syndrome is a rare X-linked disorder, lethal in males, that comprises microphthalmia, congenital cataracts, congenital heart defect, canine radiculomegaly, and digital anomalies. We report on a 7-year-old girl who was referred for muscular hypotonia, with clinical features of Duchenne muscular dystrophy, including elevated serum creatine phosphokinase, pseudohypertrophy of calf muscles, and muscle weakness, which became evident at 3 years of age. In addition, she had multiple congenital anomalies including atrial septal defect, cataracts, dental and digital anomalies, a constellation that suggested the diagnosis of oculo-facio-cardio-dental syndrome, a condition caused by mutations in BCOR. Immunohistochemistry and Western blot analysis of muscle, and mutation analysis of DMD showed a maternally inherited deletion of exons 30-43, confirming the diagnosis of Duchenne muscular dystrophy. Studies of lymphocytes showed essentially complete skewing of X-inactivation. Mutation analysis of BCOR revealed a de novo frameshift mutation (c.1005delC). Thus, we report for the first time on an individual with the co-occurrence of Duchenne muscular dystrophy and oculo-facio-cardio-dental syndrome. PMID:19449433

  7. Dosage Compensation of X-Linked Muller Element F Genes but Not X-Linked Transgenes in the Australian Sheep Blowfly

    PubMed Central

    Linger, Rebecca J.; Belikoff, Esther J.; Scott, Maxwell J.

    2015-01-01

    In most animals that have X and Y sex chromosomes, chromosome-wide mechanisms are used to balance X-linked gene expression in males and females. In the fly Drosophila melanogaster, the dosage compensation mechanism also generally extends to X-linked transgenes. Over 70 transgenic lines of the Australian sheep blowfly Lucilia cuprina have been made as part of an effort to develop male-only strains for a genetic control program of this major pest of sheep. All lines carry a constitutively expressed fluorescent protein marker gene. In all 12 X-linked lines, female larvae show brighter fluorescence than male larvae, suggesting the marker gene is not dosage compensated. This has been confirmed by quantitative RT-PCR for selected lines. To determine if endogenous X-linked genes are dosage compensated, we isolated 8 genes that are orthologs of genes that are on the fourth chromosome in D. melanogaster. Recent evidence suggests that the D. melanogaster fourth chromosome, or Muller element F, is the ancestral X chromosome in Diptera that has reverted to an autosome in Drosophila species. We show by quantitative PCR of male and female DNA that 6 of the 8 linkage group F genes reside on the X chromosome in L. cuprina. The other two Muller element F genes were found to be autosomal in L. cuprina, whereas two Muller element B genes were found on the same region of the X chromosome as the L. cuprina orthologs of the D. melanogaster Ephrin and gawky genes. We find that the L. cuprina X chromosome genes are equally expressed in males and females (i.e., fully dosage compensated). Thus, unlike in Drosophila, it appears that the Lucilia dosage compensation system is specific for genes endogenous to the X chromosome and cannot be co-opted by recently arrived transgenes. PMID:26506426

  8. Dosage Compensation of X-Linked Muller Element F Genes but Not X-Linked Transgenes in the Australian Sheep Blowfly.

    PubMed

    Linger, Rebecca J; Belikoff, Esther J; Scott, Maxwell J

    2015-01-01

    In most animals that have X and Y sex chromosomes, chromosome-wide mechanisms are used to balance X-linked gene expression in males and females. In the fly Drosophila melanogaster, the dosage compensation mechanism also generally extends to X-linked transgenes. Over 70 transgenic lines of the Australian sheep blowfly Lucilia cuprina have been made as part of an effort to develop male-only strains for a genetic control program of this major pest of sheep. All lines carry a constitutively expressed fluorescent protein marker gene. In all 12 X-linked lines, female larvae show brighter fluorescence than male larvae, suggesting the marker gene is not dosage compensated. This has been confirmed by quantitative RT-PCR for selected lines. To determine if endogenous X-linked genes are dosage compensated, we isolated 8 genes that are orthologs of genes that are on the fourth chromosome in D. melanogaster. Recent evidence suggests that the D. melanogaster fourth chromosome, or Muller element F, is the ancestral X chromosome in Diptera that has reverted to an autosome in Drosophila species. We show by quantitative PCR of male and female DNA that 6 of the 8 linkage group F genes reside on the X chromosome in L. cuprina. The other two Muller element F genes were found to be autosomal in L. cuprina, whereas two Muller element B genes were found on the same region of the X chromosome as the L. cuprina orthologs of the D. melanogaster Ephrin and gawky genes. We find that the L. cuprina X chromosome genes are equally expressed in males and females (i.e., fully dosage compensated). Thus, unlike in Drosophila, it appears that the Lucilia dosage compensation system is specific for genes endogenous to the X chromosome and cannot be co-opted by recently arrived transgenes. PMID:26506426

  9. Mutations in the RPGR gene cause X-linked cone dystrophy.

    PubMed

    Yang, Zhenglin; Peachey, Neal S; Moshfeghi, Darius M; Thirumalaichary, Sukanya; Chorich, Lou; Shugart, Yin Y; Fan, Keke; Zhang, Kang

    2002-03-01

    X-linked cone dystrophy is a type of hereditary retinal degeneration characterized by a progressive dysfunction of the day vision or photopic (cone) system with preservation of night vision or scotopic (rod) function. The disease presents with a triad of photophobia, loss of color vision and reduced central vision. This phenotype is distinct from retinitis pigmentosa (RP) in which there are prominent night and peripheral vision disturbances. X-linked cone dystrophy is a genetically heterogeneous disorder, with linkage to loci on Xp11.4--Xp21.1 (COD1, OMIM 304020) and Xq27 (COD2, OMIM 303800). COD1 maps to a region that harbors the RPGR gene, mutations in which account for >70% of patients with X-linked RP. The majority of these mutations reside in one purine-rich exon, ORF15, encoding 567 amino acids with a repetitive domain rich in glutamic acid residues. We mapped two families with X-linked cone dystrophy to the COD1 locus and identified two distinct mutations in ORF15 in the RPGR gene (ORF15+1343_1344delGG and ORF15+694_708del15) leading to a frame-shift and premature termination of translation in one case and a deletion of five amino acids in another. Consistent with expression of RPGR in rods and cones, our results show that mutations in RPGR, in addition to X-linked RP, can also cause cone-specific degeneration.

  10. X-linked congenital ataxia: a new locus maps to Xq25-q27.1.

    PubMed

    Zanni, Ginevra; Bertini, Enrico; Bellcross, Cecelia; Nedelec, Brigitte; Froyen, Guy; Neuhäuser, Gerhard; Opitz, John M; Chelly, Jamel

    2008-03-01

    We report clinical and molecular studies on a large American family of Norwegian descent with X-linked nonprogressive congenital ataxia (XCA) in six affected males over three generations. Neuroimaging showed global cerebellar hypoplasia without evidence of supratentorial anomalies. Linkage analysis resulted in a maximum LOD score Z = 3.44 for marker DXS1192 at Theta = 0.0 with flanking markers DXS1047 and DXS1227 defining a region of 12 cM in Xq25-q27.1. The clinical and neuroradiological findings in the present family are very similar to those described in two reported X-linked families [Illarioshkin et al., 1996; Bertini et al., 2000]; however, the newly identified locus does not overlap with the one defined previously, indicating that there are at least two genes responsible for this rare form of X-linked congenital cerebellar ataxia with normal intelligence.

  11. Management of Red Teeth in an International Patient with X-Linked Adrenoleukodystrophy.

    PubMed

    Petrova, Elena; Miller, Weston P; Myers, Sandra L; Karp, Jeffrey M

    2015-01-01

    Childhood cerebral X-linked adrenoleukodystrophy is a progressive, central nervous system, and endocrine disorder that typically leads to total neurologic disability and, eventually, death without appropriate, timely medical therapy. Hematopoietic stem cell transplantation has been found effective in slowing cerebral deterioration and improving long-term survival. The purpose of this case report was to describe the multidisciplinary management of red, discolored, pulpally treated primary molars identified in a nine-year-old Russian boy with childhood cerebral X-linked adrenoleukodystrophy preparing for myeloablative conditioning chemotherapy followed by hematopoietic stem cell transplantation.

  12. A Case Report of X-Linked Hyperimmunoglobulin M Syndrome with Lipoma Arborescens of Knees

    PubMed Central

    Yao, Zhongqiang; Liu, Xiangyuan

    2016-01-01

    The X-linked hyperimmunoglobulin M syndrome (HIGM), caused by mutations in the CD40LG gene, is a kind of primary immunodeficiency disease (PID). Patients with X-linked HIGM are susceptible to infection as well as autoimmune diseases. Lipoma arborescens (LA) is a rare benign tumor, of which the pathogenesis mechanism has not been clearly understood. We report a case of HIGM combined with LA in a 22-year-old male patient. A new deletion mutation of CD40LG gene was detected in this case. The possible relationship between HIGM and LA was also discussed.

  13. Localisation of the MRX3 gene for non-specific X linked mental retardation.

    PubMed Central

    Gedeon, A; Kerr, B; Mulley, J; Turner, G

    1991-01-01

    A family is described with five affected males segregating a new gene for non-specific X linked mental retardation (MRX). Linkage analysis localised the gene at Xq28-qter. The maximum lod score was 2.89 with DXS52 (St14) at theta = 0.0. A recombinant was observed with DXS304 (U6.2) defining the proximal limit to the localisation. No evidence for linkage was determined using markers at several points along the remainder of the X chromosome, including the regions known to contain MRX1 and MRX2. This delineates the third gene for non-specific X linked mental retardation, MRX3. Images PMID:1870093

  14. Abnormal Cortex-Muscle Interactions in Subjects with X-linked Kallmann's Syndrome and Mirror Movements

    ERIC Educational Resources Information Center

    Farmer, S. F.; Harrison, L. M.; Mayston, M. J.; Parekh, A.; James, L. M.; Stephens, J. A.

    2004-01-01

    X-linked Kallmann's (XKS) subjects, who display mirror movements, have abnormal corticospinal tracts which innervate motoneurons of the left and right distal muscles of the upper limb. The size of the abnormal ipsilateral projection is variable. We have used coherence and cumulant analysis between EEG and first dorsal interosseous muscle (1DI) EMG…

  15. X-linked genes evolve higher codon bias in Drosophila and Caenorhabditis.

    PubMed

    Singh, Nadia D; Davis, Jerel C; Petrov, Dmitri A

    2005-09-01

    Comparing patterns of molecular evolution between autosomes and sex chromosomes (such as X and W chromosomes) can provide insight into the forces underlying genome evolution. Here we investigate patterns of codon bias evolution on the X chromosome and autosomes in Drosophila and Caenorhabditis. We demonstrate that X-linked genes have significantly higher codon bias compared to autosomal genes in both Drosophila and Caenorhabditis. Furthermore, genes that become X-linked evolve higher codon bias gradually, over tens of millions of years. We provide several lines of evidence that this elevation in codon bias is due exclusively to their chromosomal location and not to any other property of X-linked genes. We present two possible explanations for these observations. One possibility is that natural selection is more efficient on the X chromosome due to effective haploidy of the X chromosomes in males and persistently low effective numbers of reproducing males compared to that of females. Alternatively, X-linked genes might experience stronger natural selection for higher codon bias as a result of maladaptive reduction of their dosage engendered by the loss of the Y-linked homologs.

  16. Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility.

    PubMed

    Lu, Xuemei; Shapiro, Joshua A; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

    2010-08-01

    Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible.

  17. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Focal dermal hypoplasia is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular, and dental malformations. We used array comparative genomic hybridization to identify a 219-kb deletion in Xp11.23 in two affected females. We sequenced genes in this region and fou...

  18. X-Linked Intellectual Disability: Unique Vulnerability of the Male Genome

    ERIC Educational Resources Information Center

    Stevenson, Roger E.; Schwartz, Charles E.

    2009-01-01

    X-linked intellectual disability (XLID) accounts for approximately 16% of males with intellectual disability (ID). This is, in part, related to the fact that males have a single X chromosome. Progress in the clinical and molecular characterization of XLID has outpaced progress in the delineation of ID due to genes on the other 22 chromosomes.…

  19. Sex Differences in Speed of Mental Rotation and the X-Linked Genetic Hypothesis.

    ERIC Educational Resources Information Center

    Thomas, Hoben; Kail, Robert

    1991-01-01

    Mental-rotation task response times from 12 studies involving 505 adults--251 males and 254 females--were used to evaluate 5 hypotheses concerning sex differences derived from an X-linked genetic model. The model assumes that task facilitation in speed of mental rotation is mediated by a recessive gene. Four hypotheses derived from the model were…

  20. Sex Differences in Spatial Ability: The X-Linked Gene Theory.

    ERIC Educational Resources Information Center

    Blatter, Patricia

    1982-01-01

    Among the many theories attempting to explain sex differences in spatial ability, one of the most highly researched is the X-linked recessive gene theory. This is a review of the major research done on that theory and shows the conflicting nature of the results. (Author)

  1. X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13.

    PubMed Central

    Raskind, W H; Wijsman, E; Pagon, R A; Cox, T C; Bawden, M J; May, B K; Bird, T D

    1991-01-01

    Molecular linkage analysis was performed on a kindred with X-linked sideroblastic anemia and ataxia. Two-point analysis with a DNA probe for phosphoglycerate kinase (PGK1), which maps to Xq13, suggested linkage to the disorder by a lod score of at least 2.60 at a recombination fraction of zero. The disease in this kindred appears to be clinically and genetically distinct from that in previously reported families with X-linked hereditary ataxia or spastic paraparesis. No mapping data are available for inherited X-linked sideroblastic anemia without neurologic abnormalities. However, structural alterations of band Xq13 may be involved in the development of idiopathic acquired sideroblastic anemia. No alterations in the restriction patterns of two X-linked genes involved in erythrocyte formation-i.e., a DNA-binding protein (GF-1) and 5-aminolevulinate synthase (ALAS)-were detected in DNA from affected males, arguing against a large deletion in either of these candidate genes. Images Figure 1 PMID:1671320

  2. Expression of the disease on female carriers of X-linked lysosomal disorders: a brief review

    PubMed Central

    2010-01-01

    Most lysosomal diseases (LD) are inherited as autosomal recessive traits, but two important conditions have X-linked inheritance: Fabry disease and Mucopolysaccharidosis II (MPS II). These two diseases show a very different pattern regarding expression on heterozygotes, which does not seem to be explained by the X-inactivation mechanism only. While MPS II heterozygotes are asymptomatic in most instances, in Fabry disease most of female carriers show some disease manifestation, which is sometimes severe. It is known that there is a major difference among X-linked diseases depending on the cell autonomy of the gene product involved and, therefore, on the occurrence of cross-correction. Since lysosomal enzymes are usually secreted and uptaken by neighbor cells, the different findings between MPS II and Fabry disease heterozygotes can also be due to different efficiency of cross-correction (higher in MPS II and lower in Fabry disease). In this paper, we review these two X-linked LD in order to discuss the mechanisms that could explain the different rates of penetrance and expressivity observed in the heterozygotes; this could be helpful to better understand the expression of X-linked traits. PMID:20509947

  3. Canine hyperlipidaemia.

    PubMed

    Xenoulis, P G; Steiner, J M

    2015-10-01

    Hyperlipidaemia refers to an increased concentration of lipids in the blood. Hyperlipidaemia is common in dogs and has recently emerged as an important clinical condition that requires a systematic diagnostic approach and appropriate treatment. Hyperlipidaemia can be either primary or secondary to other diseases. Secondary hyperlipidaemia is the most common form in dogs, and it can be a result of endocrine disorders, pancreatitis, cholestasis, protein-losing nephropathy, obesity, as well as other conditions and the use of certain drugs. Primary hyperlipidaemia is less common in the general canine population but it can be very common within certain breeds. Hypertriglyceridaemia of Miniature Schnauzers is the most common form of primary hyperlipidaemia in dogs but other breeds are also affected. Possible complications of hyperlipidaemia in dogs include pancreatitis, liver disease, atherosclerosis, ocular disease and seizures. Management of primary hyperlipidaemia in dogs is achieved by administration of ultra low-fat diets with or without the administration of lipid lowering drugs such as omega-3 fatty acids, fibrates, niacin and statins. PMID:26456868

  4. The mouse rumpshaker mutation of the proteolipid protein in human X-linked recessive spastic paraplegia

    SciTech Connect

    Kobayashi, H.; Hoffman, E.P.; Matise, T.C.

    1994-09-01

    X-linked recessive spastic paraplegia is a rare neurodegenerative disorder characterized by slowly progressive weakness and spasticity of the lower extremities. We have recently genetically analyzed the original X-linked recessive spastic paraplegia family reported by Johnston and McKusick in 1962. We employed a fluorescent multiplex CA repeat strategy using a 22 locus, 10 cM framework map of the human X chromosome and localized the gene within a 36 cM region of Xq2l.3-q24 which includes the PLP locus. Saugier-Veber et al. recently reported a point mutation (His139Tyr) in exon 3B of the PLP gene in an X-linked recessive spastic paraplegia family (SPG2). This family shows no optic atrophy, in contrast to the family we have studied. This data showed that SPG2 and Pelizaeus-Merzbacher disease were allelic disorders. We investigated the PLP gene as a candidate gene for the original X-linked recessive spastic paraplegia family using SSCP and direct sequencing methods. We found a point mutation (T to C) in exon 4 of affected males which alters the amino-acid (Ile to Thr) at residue 186. This change was absent in the unaffected males of the family and in 40 unrelated control females (80 X chromosomes). Surprisingly, this mutation is identical to the mutation previously identified in the rumpshaker mouse model. The complete homology between both the mouse and human PLP sequence, and the mouse rumpshaker mutation and human spastic paraplegia mutation in our family, permit direct parallels to be drawn with regards to pathophysiology. Our data indicates that the well-documented and striking clinical differences between Pelizaeus-Merzbacher disease and X-linked recessive spastic paraplegia is due to the specific effect of different mutations of the human PLP gene on oligodendrocyte differentiation and development and on later myelin production and maintenance.

  5. Fine Mapping of Dominant X-Linked Incompatibility Alleles in Drosophila Hybrids

    PubMed Central

    Matute, Daniel R.; Gavin-Smyth, Jackie

    2014-01-01

    Sex chromosomes have a large effect on reproductive isolation and play an important role in hybrid inviability. In Drosophila hybrids, X-linked genes have pronounced deleterious effects on fitness in male hybrids, which have only one X chromosome. Several studies have succeeded at locating and identifying recessive X-linked alleles involved in hybrid inviability. Nonetheless, the density of dominant X-linked alleles involved in interspecific hybrid viability remains largely unknown. In this report, we study the effects of a panel of small fragments of the D. melanogaster X-chromosome carried on the D. melanogaster Y-chromosome in three kinds of hybrid males: D. melanogaster/D. santomea, D. melanogaster/D. simulans and D. melanogaster/D. mauritiana. D. santomea and D. melanogaster diverged over 10 million years ago, while D. simulans (and D. mauritiana) diverged from D. melanogaster over 3 million years ago. We find that the X-chromosome from D. melanogaster carries dominant alleles that are lethal in mel/san, mel/sim, and mel/mau hybrids, and more of these alleles are revealed in the most divergent cross. We then compare these effects on hybrid viability with two D. melanogaster intraspecific crosses. Unlike the interspecific crosses, we found no X-linked alleles that cause lethality in intraspecific crosses. Our results reveal the existence of dominant alleles on the X-chromosome of D. melanogaster which cause lethality in three different interspecific hybrids. These alleles only cause inviability in hybrid males, yet have little effect in hybrid females. This suggests that X-linked elements that cause hybrid inviability in males might not do so in hybrid females due to differing sex chromosome interactions. PMID:24743238

  6. A family with X-linked anophthalmia: exclusion of SOX3 as a candidate gene.

    PubMed

    Slavotinek, Anne; Lee, Stephen S; Hamilton, Steven P

    2005-10-01

    We report on a four-generation family with X-linked anophthalmia in four affected males and show that this family has LOD scores consistent with linkage to Xq27, the third family reported to be linked to the ANOP1 locus. We sequenced the SOX3 gene at Xq27 as a candidate gene for the X-linked anophthalmia based on the high homology of this gene to SOX2, a gene previously mutated in bilateral anophthlamia. However, no amino acid sequence alterations were identified in SOX3. We have improved the definition of the phenotype in males with anophthalmia linked to the ANOP1 locus, as microcephaly, ocular colobomas, and severe renal malformations have not been described in families linked to ANOP1.

  7. A Common Founder Mutation in the EDA-A1 Gene in X-Linked Hypodontia

    PubMed Central

    Kurban, Mazen; Michailidis, Eleni; Wajid, Muhammad; Shimomura, Yutaka; Christiano, Angela M.

    2010-01-01

    Background X-linked recessive hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a rare genodermatosis characterized clinically by developmental abnormalities affecting the teeth, hair and sweat glands. Mutations in the EDA-A1 gene have been associated with XLHED. Recently, mutations in the EDA-A1 gene have also been implicated in isolated X-linked recessive hypodontia (XLRH; OMIM 313500). Methods We analyzed the DNA from members of 3 unrelated Pakistani families with XLRH for mutations in the EDA-A1 gene through direct sequencing and performed haplotype analysis. Results We identified a common missense mutation in both families designated c.1091T→C (p.M364T). Haplotype analysis revealed that this is a founder mutation in the 3 families. Conclusion XLHED is a syndrome with variable clinical presentations that contain a spectrum of findings, including hypodontia. We suggest that XLRH should be grouped under XLHED as both share several phenotypic and genotypic similarities. PMID:20628232

  8. Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis.

    PubMed

    Bush, Ronald A; Wei, Lisa L; Sieving, Paul A

    2015-08-01

    Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in males. X-linked retinoschisis (XLRS) typically affects young males; however, progressive vision loss continues throughout life. Although discovered in 1898 by Haas in two brothers, the underlying biology leading to blindness has become apparent only in the last 15 years with the advancement of human genetic analyses, generation of XLRS animal models, and the development of ocular monitoring methods such as the electroretinogram and optical coherence tomography. It is now recognized that retinoschisis results from cyst formations within the retinal layers that interrupt normal visual neurosignaling and compromise structural integrity. Mutations in the human retinoschisin gene have been correlated with disease severity of the human XLRS phenotype. Introduction of a normal human retinoschisin cDNA into retinoschisin knockout mice restores retinal structure and improves neural function, providing proof-of-concept that gene replacement therapy is a plausible treatment for XLRS.

  9. X-linked ichthyosis without STS deficiency: Clinical, genetical, and molecular studies

    SciTech Connect

    Robledo, R.; Melis, P.; Schillinger, E.; Siniscalco, M.

    1995-11-06

    We report on a Sardinian pedigree with congenital ichthyosis associated with normal levels of steroid sulfatase and a normal molecular pattern, as detectable with a cDNA probe for the steroid sulfatase (STS) gene. Though the pattern of transmission of the disease is consistent with X-linked recessive inheritance, this form of ichthyosis was found to segregate independently of genetic polymorphisms detected by probes of the region Xp22.3, where the STS locus has been mapped. The search for close genetic linkages with other polymorphic markers scattered along the entire X chromosome has so far been fruitless. For the time being, the main conclusion derived from these data is that STS deficiency is not a sine qua non for X-linked ichthyosis which may also result from a mutational event at an X-chromosomal site genetically unlinked to the STS locus. 16 refs., 4 figs.

  10. X-linked ocular albinism and sensorineural deafness: Linkage to Xp22. 3

    SciTech Connect

    Winship, I.M.; Babaya, M.; Ramesar, R.S. )

    1993-11-01

    X-linked ocular albinism with late-onset sensorineural deafness (OASD) is an autonomous disorder that poses significant clinical problems, causing affected individuals to be blind and deaf by early middle age. Classical X-linked ocular albinism (without deafness; OA1) has recently been linked to markers in the Xp22.2-Xp22.3 region of the human genome. In the present report, a large South African family with OASD was investigated at the molecular level and tight linkage was found to the DXS452 locus at Xp22.3 using 25 informative meioses, with a maximum lod score of 7.1 at a recombination fraction of 0.00. These findings suggest that OA1 and OASD are allelic variants or that they may be due to contiguous gene defects. 12 refs., 1 fig.

  11. Sporothrix schenckii lymphadentitis in a male with X-linked chronic granulomatous disease.

    PubMed

    Trotter, Jessica R; Sriaroon, Panida; Berman, David; Petrovic, Aleksandra; Leiding, Jennifer W

    2014-01-01

    Sporothrix schenckii lymphadenitis was identified in a 33 month old male with X-linked chronic granulomatous disease (CGD). S. schenckii is a dimorphic catalase producing fungus found in the soil of temperate and tropical climates. Host defense against S. schenckii relies primarily on innate and cellular responses and gp91(phox-/-) mice are susceptible to disseminated infection. This case represents the first report of susceptibility to sporotrichosis in a patient with CGD.

  12. Hereditary motor-sensory neuropathy (HMSN): possible X-linked dominant inheritance.

    PubMed

    Phillips, L H; Kelly, T E; Schnatterly, P; Parker, D

    1985-04-01

    The inheritance of the hereditary motor and sensory neuropathies (HMSN) is usually autosomal dominant. We studied a kinship with a pattern of X-linked dominant inheritance. The phenotype was similar to HMSN of the "intermediate" type. Men were more severely affected than women, and hypertrophic nerves were not found. Nerve conduction was very slow in men, but it was mildly slow or normal in women. No male-to-male transmission was found in six generations.

  13. Nonspecific X-linked mental retardation with macrocephaly and obesity: A further family

    SciTech Connect

    Baraitser, M.; Reardon, W.; Vijeratnam, S.

    1995-07-03

    The phenotypic nonspecificity of many forms of X-linked mental retardation has hampered attempts to classify them into clinically homogeneous groups. One such condition, described by Clark and Baraitser, has been the subject of a single pedigree report to date. We now describe a further pedigree whose affected members share many manifestations with those reported by Clark and Baraitser, and we consider the possible distinction between this condition and Atkin-Flaitz syndrome. 9 refs., 4 figs., 1 tab.

  14. CRISPR/Cas9 Promotes Functional Study of Testis Specific X-Linked Gene In Vivo

    PubMed Central

    Jiang, Xue; Chen, Yuxi; Zhang, Zhen; Zhang, Xiya; Liang, Puping; Zhan, Shaoquan; Cao, Shanbo; Songyang, Zhou; Huang, Junjiu

    2015-01-01

    Mammalian spermatogenesis is a highly regulated multistage process of sperm generation. It is hard to uncover the real function of a testis specific gene in vitro since the in vitro model is not yet mature. With the development of the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9) system, we can now rapidly generate knockout mouse models of testis specific genes to study the process of spermatogenesis in vivo. SYCP3-like X-linked 2 (SLX2) is a germ cell specific component, which contains a Cor1 domain and belongs to the XLR (X-linked, lymphocyte regulated) family. Previous studies suggested that SLX2 might play an important role in mouse spermatogenesis based on its subcellular localization and interacting proteins. However, the function of SLX2 in vivo is still elusive. Here, to investigate the functions of SLX2 in spermatogenesis, we disrupted the Slx2 gene by using the CRISPR/Cas9 system. Since Slx2 is a testis specific X-linked gene, we obtained knockout male mice in the first generation and accelerated the study process. Compared with wild-type mice, Slx2 knockout mice have normal testis and epididymis. Histological observation of testes sections showed that Slx2 knockout affected none of the three main stages of spermatogenesis: mitosis, meiosis and spermiogenesis. In addition, we further confirmed that disruption of Slx2 did not affect the number of spermatogonial stem cells, meiosis progression or XY body formation by immunofluorescence analysis. As spermatogenesis was normal in Slx2 knockout mice, these mice were fertile. Taken together, we showed that Slx2 itself is not an essential gene for mouse spermatogenesis and CRISPR/Cas9 technique could speed up the functional study of testis specific X-linked gene in vivo. PMID:26599493

  15. Molecular genetic analysis of patients with sporadic and X-linked infantile nystagmus

    PubMed Central

    Zhao, Hui; Huang, Xiu-Feng; Zheng, Zhi-Li; Deng, Wen-Li; Lei, Xin-Lan; Xing, Dong-Jun; Ye, Liang; Xu, Su-Zhong; Chen, Jie; Zhang, Fang; Yu, Xin-Ping; Jin, Zi-Bing

    2016-01-01

    Objectives Infantile nystagmus (IN) is a genetically heterogeneous condition characterised by involuntary rhythmic oscillations of the eyes accompanied by different degrees of vision impairment. Two genes have been identified as mainly causing IN: FRMD7 and GPR143. The aim of our study was to identify the genetic basis of both sporadic IN and X-linked IN. Design Prospective analysis. Patients Twenty Chinese patients, including 15 sporadic IN cases and 5 from X-linked IN families, were recruited and underwent molecular genetic analysis. We first performed PCR-based DNA sequencing of the entire coding region and the splice junctions of the FRMD7 and GPR143 genes in participants. Mutational analysis and co-segregation confirmation were then performed. Setting All clinical examinations and genetic experiments were performed in the Eye Hospital of Wenzhou Medical University. Results Two mutations in the FRMD7 gene, including one novel nonsense mutation (c.1090C>T, p.Q364X) and one reported missense mutation (c.781C>G, p.R261G), were identified in two of the five (40%) X-linked IN families. However, none of putative mutations were identified in FRMD7 or GPR143 in any of the sporadic cases. Conclusions The results suggest that mutations in FRMD7 appeared to be the major genetic cause of X-linked IN, but not of sporadic IN. Our findings provide further insights into FRMD7 mutations, which could be helpful for future genetic diagnosis and genetic counselling of Chinese patients with nystagmus. PMID:27036142

  16. X-linked adrenoleukodystrophy with non-diagnostic plasma very long chain fatty acids.

    PubMed Central

    Kennedy, C R; Allen, J T; Fensom, A H; Steinberg, S J; Wilson, R

    1994-01-01

    Measurement of plasma very long chain fatty acids is widely recognised as a sensitive screening test for X-linked adrenoleukodystrophy (X-ALD). This test has particular importance because of the highly variable clinical expression of X-ALD. In this affected family the progressive childhood form of X-ALD was accompanied by "non-diagnostic" concentrations of plasma very long chain fatty acids. The implications for diagnosis of X-ALD are discussed. PMID:8006665

  17. Peroxisomal. beta. -oxidation enzyme proteins in adrenoleukodystrophy: distinction between x-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy

    SciTech Connect

    Chen, W.W.; Watkins, P.A.; Osumi, T.; Hashimoto, T.; Moser, H.W.

    1987-03-01

    Very long chain fatty acids, which accumulate in plasma and tissues in x-linked adrenoleukodystrophy (ALD), neonatal ALD, and the Zellweger cerebrohepatorenal syndrome, are degraded by the peroxisomal ..beta..-oxidation pathway, consisting of acyl-CoA oxidase, the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, and ..beta..-ketothiolase. A marked deficiency of all three enzyme proteins was reported in livers from patients with the Zellweger syndrome, a disorder in which peroxisomes are decreased or absent. Peroxisomes are not as markedly decreased in neonatal ALD and appear normal in x-linked ALD. Immunoblot analysis of the peroxisomal ..beta..-oxidation enzymes revealed an almost complete lack of the bifunctional enzymes in neonatal ALD liver, similar to the finding in Zellweger tissues. In contrast, acyl-CoA oxidase and ..beta..-ketothiolase were present in neonatal ALD liver, although the thiolase appeared to be in precursor form (2-3 kDa larger than the mature enzyme) in neonatal ALD. Unlike either neonatal ALD or Zellweger syndrome, all three peroxisomal ..beta..-oxidation enzymes were present in x-linked ALD liver. Despite the absence in neonatal ALD liver of bifunctional enzyme protein, its mRNA was detected by RNA blot analysis in fibroblasts from these patients. These observations suggest that lack of bifunctional enzyme protein in neonatal ALD results from either abnormal translation of the mRNA or degradation of the enzyme prior to its entry into peroxisomes.

  18. X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations.

    PubMed

    McCauley, Joanna; Masand, Navta; McGowan, Ruth; Rajagopalan, Sulekha; Hunter, Alasdair; Michaud, Jacques L; Gibson, Kate; Robertson, Jeremy; Vaz, Fiona; Abbs, Stephen; Holden, Simon T

    2011-10-01

    X-linked VACTERL-hydrocephalus syndrome (X-linked VACTERL-H) is a rare disorder caused by mutations in the gene FANCB which underlies Fanconi Anemia (FA) complementation group B. Cells from affected males have increased chromosome breakage on exposure to DNA cross-linking agents. Only five FANCB mutations found in six affected males, including an affected uncle and nephew, have been reported. We have identified FANCB mutations in a further four affected families. The VACTERL-H phenotype segregates as an X-linked recessive trait in three of these. Each mutation is predicted to truncate the FANCB open reading frame and results in highly skewed X-inactivation in unaffected carrier females. Phenotypic data were available on six affected males. Comparison of the clinical findings in our patients with published clinical data (total 12 patients) shows that ventriculomegaly, bilateral absent thumbs and radii, vertebral defects, renal agenesis, and growth retardation are the major phenotypic signs in affected males. Less frequent are brain, pituitary, ear and eye malformations, gastrointestinal atresias (esophageal, duodenal and anal), tracheoesophageal fistula, lung segmentation defects, and small genitalia. Three of six of our patients survived the perinatal period. One boy lived up to 2 years 10 months but developed aplastic anemia and died of renal failure. These data show that loss-of-function FANCB mutations result in a recognizable, multiple malformation phenotype in hemizygous males for which we propose clinical criteria to aid diagnosis. PMID:21910217

  19. Meiotic drive impacts expression and evolution of x-linked genes in stalk-eyed flies.

    PubMed

    Reinhardt, Josephine A; Brand, Cara L; Paczolt, Kimberly A; Johns, Philip M; Baker, Richard H; Wilkinson, Gerald S

    2014-01-01

    Although sex chromosome meiotic drive has been observed in a variety of species for over 50 years, the genes causing drive are only known in a few cases, and none of these cases cause distorted sex-ratios in nature. In stalk-eyed flies (Teleopsis dalmanni), driving X chromosomes are commonly found at frequencies approaching 30% in the wild, but the genetic basis of drive has remained elusive due to reduced recombination between driving and non-driving X chromosomes. Here, we used RNAseq to identify transcripts that are differentially expressed between males carrying either a driving X (XSR) or a standard X chromosome (XST), and found hundreds of these, the majority of which are X-linked. Drive-associated transcripts show increased levels of sequence divergence (dN/dS) compared to a control set, and are predominantly expressed either in testes or in the gonads of both sexes. Finally, we confirmed that XSR and XST are highly divergent by estimating sequence differentiation between the RNAseq pools. We found that X-linked transcripts were often strongly differentiated (whereas most autosomal transcripts were not), supporting the presence of a relatively large region of recombination suppression on XSR presumably caused by one or more inversions. We have identified a group of genes that are good candidates for further study into the causes and consequences of sex-chromosome drive, and demonstrated that meiotic drive has had a profound effect on sequence evolution and gene expression of X-linked genes in this species.

  20. X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations.

    PubMed

    McCauley, Joanna; Masand, Navta; McGowan, Ruth; Rajagopalan, Sulekha; Hunter, Alasdair; Michaud, Jacques L; Gibson, Kate; Robertson, Jeremy; Vaz, Fiona; Abbs, Stephen; Holden, Simon T

    2011-10-01

    X-linked VACTERL-hydrocephalus syndrome (X-linked VACTERL-H) is a rare disorder caused by mutations in the gene FANCB which underlies Fanconi Anemia (FA) complementation group B. Cells from affected males have increased chromosome breakage on exposure to DNA cross-linking agents. Only five FANCB mutations found in six affected males, including an affected uncle and nephew, have been reported. We have identified FANCB mutations in a further four affected families. The VACTERL-H phenotype segregates as an X-linked recessive trait in three of these. Each mutation is predicted to truncate the FANCB open reading frame and results in highly skewed X-inactivation in unaffected carrier females. Phenotypic data were available on six affected males. Comparison of the clinical findings in our patients with published clinical data (total 12 patients) shows that ventriculomegaly, bilateral absent thumbs and radii, vertebral defects, renal agenesis, and growth retardation are the major phenotypic signs in affected males. Less frequent are brain, pituitary, ear and eye malformations, gastrointestinal atresias (esophageal, duodenal and anal), tracheoesophageal fistula, lung segmentation defects, and small genitalia. Three of six of our patients survived the perinatal period. One boy lived up to 2 years 10 months but developed aplastic anemia and died of renal failure. These data show that loss-of-function FANCB mutations result in a recognizable, multiple malformation phenotype in hemizygous males for which we propose clinical criteria to aid diagnosis.

  1. Localization of Impacted Canines

    PubMed Central

    Mehrotra, Praveen; Bhagchandani, Jitendra; Singh, Ashish; Garg, Aarti; Kumar, Snehi; Sharma, Ashish; Yadav, Harsh

    2015-01-01

    Impaction of maxillary canines is a frequently encountered clinical problem. The impaction of canine can be prevented in some situationsif the canine displacement is diagnosed in the early mixed dentition period and this would be extremely useful for the clinician. Hence,it is very important to focus on the means of early diagnosis and interception of this clinical situation. In the present article, the differentmodalities used to diagnose the impacted canine are reviewed with an insight into current 3-D modalities. PMID:25738100

  2. Allelic variation in the squirrel monkey x-linked color vision gene: biogeographical and behavioral correlates.

    PubMed

    Cropp, Susan; Boinski, Sue; Li, Wen-Hsiung

    2002-06-01

    Most Neotropical primate species possess a polymorphic X-linked and a monomorphic autosomal color vision gene. Consequently, populations are composed of both dichromatics and trichromatics. Most theories on the maintenance of this genetic system revolve around possible advantages for foraging ecology. To examine the issue from a different angle, we compared the numbers and relative frequencies of alleles at the X-linked locus among three species of Saimiri representing a wide range of geographical and behavioral variation in the genus. Exons 3, 4, and 5 of the X-linked opsin gene were sequenced for a large number of X chromosomes for all three species. Several synonymous mutations were detected in exons 4 and 5 for the originally reported alleles but only a single nonsynonymous change was detected. Two alleles were found that appeared to be the result of recombination events. The low occurrence of recombinant alleles and absence of mutations in the amino acids critical for spectral tuning indicates that stabilizing selection acts to maintain the combinations of critical sites specific to each allele. Allele frequencies were approximately the same for all Saimiri species, with a slight but significant difference between S. boliviensis and S. oerstedii. No apparent correlation exists between allele frequencies and behavioral or biogeographical differences between species, casting doubt on the speculation that the spectral sensitivities of the alleles have been maintained because they are specifically well-tuned to Saimiri visual ecology. Rather, the spectral tuning peaks might have been maintained because they are as widely spaced as possible within the limited range of middlewave to longwave spectra useful to all primates. This arrangement creates a balance between maximizing the distance between spectral tuning peaks (allowing the color opponency of the visual system to distinguish between peaks) and maximizing the number of alleles within a limited range (yielding

  3. Meiotic Drive Impacts Expression and Evolution of X-Linked Genes in Stalk-Eyed Flies

    PubMed Central

    Reinhardt, Josephine A.; Brand, Cara L.; Paczolt, Kimberly A.; Johns, Philip M.; Baker, Richard H.; Wilkinson, Gerald S.

    2014-01-01

    Although sex chromosome meiotic drive has been observed in a variety of species for over 50 years, the genes causing drive are only known in a few cases, and none of these cases cause distorted sex-ratios in nature. In stalk-eyed flies (Teleopsis dalmanni), driving X chromosomes are commonly found at frequencies approaching 30% in the wild, but the genetic basis of drive has remained elusive due to reduced recombination between driving and non-driving X chromosomes. Here, we used RNAseq to identify transcripts that are differentially expressed between males carrying either a driving X (XSR) or a standard X chromosome (XST), and found hundreds of these, the majority of which are X-linked. Drive-associated transcripts show increased levels of sequence divergence (dN/dS) compared to a control set, and are predominantly expressed either in testes or in the gonads of both sexes. Finally, we confirmed that XSR and XST are highly divergent by estimating sequence differentiation between the RNAseq pools. We found that X-linked transcripts were often strongly differentiated (whereas most autosomal transcripts were not), supporting the presence of a relatively large region of recombination suppression on XSR presumably caused by one or more inversions. We have identified a group of genes that are good candidates for further study into the causes and consequences of sex-chromosome drive, and demonstrated that meiotic drive has had a profound effect on sequence evolution and gene expression of X-linked genes in this species. PMID:24832132

  4. A new nonsyndromic X-linked sensorineural hearing impairment linked to Xp21.2

    SciTech Connect

    Lalwani, A.K.; Brister, J.R.; Fex, J.; Grundfast, K.M.; Pikus, A.T.; Ploplis, B.; San Agustin, T.; Skarka, H.; Wilcox, E.R.

    1994-10-01

    X-linked deafness is a rare cause of hereditary hearing impairment. We have identified a family with X-linked dominant sensorineural hearing impairment, characterized by incomplete penetrance and variable expressivity in carrier females, that is linked to the Xp21.2, which contains the Duchenne muscular dystrophy (DMD) locus. The auditory impairment in affected males was congenital, bilateral, profound, sensorineural, affecting all frequencies, and without evidence of radiographic abnormality of the temporal bone. Adult carrier females manifested bilateral, mild-to-moderate high-frequency sensorineural hearing impairment of delayed onset during adulthood. Eighteen commercially available polymorphic markers from the X chromosome, generating a 10-15-cM map, were initially used for identification of a candidate region. DXS997, located within the DMD gene, generated a two-point LOD score of 2.91 at {theta} = 0, with every carrier mother heterozygous at this locus. Recombination events at DXS992 (located within the DMD locus, 3{prime} to exon 50 of the dystrophin gene) and at DXS1068 (5{prime} to the brain promoter of the dystrophin gene) were observed. No recombination events were noted with the following markers within the DMD locus: 5{prime}DYS II, intron 44, DXS997, and intron 50. There was no clinical evidence of Duchenne or Becker muscular dystrophy in any family member. It is likely that this family represents a new locus on the X chromosome, which when mutated results in nonsyndromic sensorineural hearing loss and is distinct from the heterogeneous group of X-linked hearing losses that have been previously described. 57 refs., 6 figs., 1 tab.

  5. Extensive germinal mosaicism in a family with X linked myotubular myopathy simulates genetic heterogeneity.

    PubMed Central

    Vincent, M C; Guiraud-Chaumeil, C; Laporte, J; Manouvrier-Hanu, S; Mandel, J L

    1998-01-01

    A family with two male cousins affected with myotubular myopathy (MTM) was referred to us for genetic counselling. Linkage analysis appeared to exclude the Xq28 region. As a gene for X linked MTM was recently identified in Xq28, we screened the obligatory carrier mothers for mutation. We found a 4 bp deletion in exon 4 of the MTM1 gene, which originated from the grandfather of the affected children and which was transmitted to three daughters. This illustrates the importance of mutation detection to avoid pitfalls in linkage analysis that may be caused by such cases of germinal mosaicism. Images PMID:9541111

  6. Premature termination of variable gene rearrangement in B lymphocytes from X-linked agammaglobulinemia.

    PubMed Central

    Schwaber, J; Chen, R H

    1988-01-01

    X-linked agammaglobulinemia (XLA) results from failure of B lymphocyte development. Immature B cells from a patient with XLA were found to produce truncated mu and delta immunoglobulin H chains encoded by D-JH-C (mu delta). The 5' terminal sequence of cDNA encoding the H chains is composed of D-JH with the characteristic GGTTTGAAG/CACTGTG consensus sequence utilized for VH gene rearrangement upstream, and a leader sequence that serves for translation of this intermediate stage of rearrangement. Failure of variable region gene rearrangement may underlie the failure of B lymphoid development in XLA. Images PMID:2838527

  7. Phenotypic Conservation in Patients With X-Linked Retinitis Pigmentosa Caused by RPGR Mutations

    PubMed Central

    Zahid, Sarwar; Khan, Naheed; Branham, Kari; Othman, Mohammad; Karoukis, Athanasios J.; Sharma, Nisha; Moncrief, Ashley; Mahmood, Mahdi N.; Sieving, Paul A.; Swaroop, Anand; Heckenlively, John R.; Jayasundera, Thiran

    2015-01-01

    IMPORTANCE For patients with X-linked retinitis pigmentosa and clinicians alike, phenotypic variability can be challenging because it complicates counseling regarding patients’ likely visual prognosis. OBJECTIVE To evaluate the clinical findings from patients with X-linked retinitis pigmentosa with 13 distinct RPGR mutations and assess for phenotypic concordance or variability. DESIGN Retrospective medical record review of data collected from 1985 to 2011. SETTING Kellogg Eye Center, University of Michigan. PATIENTS A total of 42 patients with X-linked retinitis pigmentosa with mutations in RPGR. Age at first visit ranged from 4 to 53 years, with follow-up ranging from 1 to 11 visits (median follow-up time, 5.5 years; range, 1.4-32.7 years, for 23 patients with >1 visit). MAIN OUTCOMES AND MEASURES Clinical data assessed for concordance included visual acuity (VA), Goldmann visual fields (GVFs), and full-field electroretinography (ERG). Electroretinography phenotype (cone-rod vs rod-cone dysfunction) was defined by the extent of photopic vs scotopic abnormality. Qualitative GVF phenotype was determined by the GVF pattern, where central or peripheral loss suggested cone or rod dysfunction, respectively. Goldmann visual fields were also quantified and compared among patients. RESULTS Each mutation was detected in 2 or more related or unrelated patients. Five mutations in 11 patients displayed strong concordance of VA, while 4 mutations in 16 patients revealed moderate concordance of VA. A definitive cone-rod or rod-cone ERG pattern consistent among patients was found in 6 of 13 mutations (46.2%); the remaining mutations were characterized by patients demonstrating both phenotypes or who had limited data or nonrecordable ERG values. Concordant GVF phenotypes (7 rod-cone pattern vs 4 cone-rod pattern) were seen in 11 of 13 mutations (84.6%). All 6 mutations displaying a constant ERG pattern within the mutation group revealed a GVF phenotype consistent with the ERG

  8. X-linked albinism-deafness syndrome and Waardenburg syndrome type II: A hypothesis

    SciTech Connect

    Zlotogora, J.

    1995-11-20

    Margolis reported on a large pedigree with a {open_quotes}new{close_quotes} X-linked syndrome of profound deafness and albinism (MIM 300700, albinism-deafness syndrome). The affected males presented with profound deafness and severe pigmentary abnormalities of the skin. At birth the skin appeared as almost albinotic except for areas of light pigmentation over the gluteal and scrotal areas, and thereafter pigmentation gradually increased over the body. Skin changes ultimately included areas of hypopigmentation and spots of hyperpigmentation. Some of the affected males also had blue irides, heterochromia, or segmental color iris changes. In carrier females, variable hearing impairment was documented without any pigmentary changes. 9 refs., 1 fig.

  9. Incontinentia pigmenti or Bloch-Sulzberger syndrome: a rare X-linked genodermatosis*

    PubMed Central

    Marques, Gabriela Franco; Tonello, Claudio Sampieri; Sousa, Juliana Martins Prazeres

    2014-01-01

    Incontinentia pigmenti is a rare X-linked genodermatosis that affects mainly female neonates. The first manifestation occurs in the early neonatal period and progresses through four stages: vesicular, verruciform, hyperpigmented and hypopigmented. Clinical features also manifest themselves through changes in the teeth, eyes, hair, central nervous system, bone structures, skeletal musculature and immune system. The authors report the case of a patient with cutaneous lesions and histological findings that are compatible with the vesicular stage, emphasizing the importance of early diagnosis and appropriate therapeutic management. PMID:24937825

  10. Characterization of three microsatellite loci linked to the canine RP3 interval.

    PubMed

    Zangerl, B; Zhang, Q; Acland, G M; Aguirre, G D

    2002-01-01

    X-linked retinitis pigmentosa (XLRP) is one of the most prevalent forms of a genetically heterogeneous group of inherited retinal disorders of man; more than 70% of XLRP families map to the RP2 or RP3 loci on the human X chromosome. Canine X-linked progressive retinal atrophy (XLPRA), observed in the Siberian husky, is the locus homologue of human RP3, but the gene responsible for XLPRA has not yet been identified. To develop polymorphic markers in the RP3 interval in dogs we have isolated microsatellites from canine BAC clones. Three tightly linked microsatellite loci, CUX20001, CUX30001, and CUX40002, have been investigated in 17 dog breeds or breed varieties. Calculated parameters of variability correspond with the number of repeats at each locus. Pedigree analyses showed tight linkage between the canine t-complex-associated testis-expressed 1-like gene (TCTE1l) and the gene ornithine carbamoyltransferase (OTC). Each microsatellite shows conservation within Canidae, and CUX20001 also amplified in Mustelidae and URSIDAE: These markers represent an important tool in the fine mapping process for the canine region homologous to the RP3 disease interval and are valuable for evaluation of conservation and homology of this region among related species.

  11. X-linked recessive type of pure spastic paraplegia in a large pedigree: absence of detectable linkage with Xg.

    PubMed Central

    Zatz, M; Penha-Serrano, C; Otto, P A

    1976-01-01

    A family with 24 males affected by an X-linked type of spastic paraplegia is reported. Twelve affected members were personally examined showing the pure form of the disease. Half of the affected males had many descendants, all normal. Linkage studies strongly suggest that this X-linked form of spastic paraplegia and Xg loci are not at a measurable distance on the X chromosome. PMID:1084423

  12. The X-linked inhibitor of apoptosis regulates long-term depression and learning rate.

    PubMed

    Gibon, Julien; Unsain, Nicolas; Gamache, Karine; Thomas, Rhalena A; De Leon, Andres; Johnstone, Aaron; Nader, Karim; Séguéla, Philippe; Barker, Philip A

    2016-09-01

    Hippocampal long-term depression (LTD) is an active form of synaptic plasticity that is necessary for consolidation of spatial memory, contextual fear memory, and novelty acquisition. Recent studies have shown that caspases (CASPs) play an important role in NMDA receptor-dependent LTD and are involved in postsynaptic remodeling and synaptic maturation. In the present study, we examined the role of X-linked inhibitor of apoptosis (XIAP), a putative endogenous CASP inhibitor, in synaptic plasticity in the hippocampus. Analysis in acute brain slices and in cultured hippocampal neurons revealed that XIAP deletion increases CASP-3 activity, enhances α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization, sharply increases LTD, and significantly reduces synapse density. In vivo behaviors related to memory were also altered in XIAP(-/-) mice, with faster acquisition of spatial object location and increased fear memory observed. Together, these results indicate that XIAP plays an important physiologic role in regulating sublethal CASP-3 activity within central neurons and thereby facilitates synaptic plasticity and memory acquisition.-Gibon, J., Unsain, N., Gamache, K., Thomas, R. A., De Leon, A., Johnstone, A., Nader, K., Séguéla, P., Barker, P. A. The X-linked inhibitor of apoptosis regulates long-term depression and learning rate.

  13. Genetic analysis of X-linked hybrid sterility in the house mouse.

    PubMed

    Storchová, Radka; Gregorová, Sona; Buckiová, Daniela; Kyselová, Vendula; Divina, Petr; Forejt, Jirí

    2004-07-01

    Hybrid sterility is a common postzygotic reproductive isolation mechanism that appears in the early stages of speciation of various organisms. Mus musculus musculus and Mus musculus domesticus represent two recently separated mouse subspecies particularly suitable for genetic studies of hybrid sterility. Here we show that the introgression of Chr X of M. m. musculus origin (PWD/Ph inbred strain, henceforth PWD) into the genetic background of the C57BL/6J (henceforth B6) inbred strain (predominantly of M. m. domesticus origin) causes male sterility. The X-linked hybrid sterility is associated with reduced testes weight, lower sperm count, and morphological abnormalities of sperm heads. The analysis of recombinant Chr Xs in sterile and fertile males as well as quantitative trait locus (QTL) analysis of several fertility parameters revealed an oligogenic nature of the X-linked hybrid sterility. The Hstx1 locus responsible for male sterility was mapped near DXMit119 in the central part of Chr X. To ensure full sterility, the PWD allele of Hstx1 has to be supported with the PWD allelic form of loci in at least one proximal and/or one distal region of Chr X. Mapping and cloning of Hstx1 and other genes responsible for sterility of B6-X PWD Y B6 males could help to elucidate the special role of Chr X in hybrid sterility and consequently in speciation.

  14. X-linked intellectual disability-associated mutations in synaptophysin disrupt synaptobrevin II retrieval.

    PubMed

    Gordon, Sarah L; Cousin, Michael A

    2013-08-21

    Synaptophysin is an integral synaptic vesicle (SV) protein that accounts for ∼10% of total SV protein cargo. Deletion of synaptophysin results in the defective retrieval of synaptobrevin II (sybII) from the plasma membrane during endocytosis, coupled with a slowing in the speed of endocytosis. Synaptophysin has been implicated in X-linked intellectual disability, with a recent study identifying four separate synaptophysin gene mutations in families affected by the disorder. To determine how these mutations may affect synaptophysin function, we expressed them in cultured neurons derived from synaptophysin knock-out mice. Two distinct truncating mutants were mislocalized throughout the axon and phenocopied the arrest of sybII retrieval in synaptophysin knock-out cultures. The remaining two mutants displayed a nerve terminal localization but did not support efficient sybII retrieval. Interestingly, one mutant fully rescued SV endocytosis kinetics, suggesting that sybII retrieval and endocytosis speed are independent from each other. These studies suggest that the efficient retrieval of sybII by synaptophysin may be key to maintaining synaptic health and perturbation of this event may contribute to the pathogenesis underlying neurodevelopmental disorders such as X-linked intellectual disability.

  15. Seventh international workshop on the fragile X and X-linked mental retardation

    SciTech Connect

    Tranebjaerg, L.; Lubs, H.A.; Borghgraef, M.; Fryns, J.P.

    1996-07-12

    The Seventh International Workshop on the Fragile X and X-linked Mental Retardation was held at the University of Tromso in Norway on August 2-5, 1995. Approximately 120 participants from 20 countries attended the Workshop. By special invitation Dr. Felix de la Cruz, who initiated the first international Workshop on fragile X, attended this Workshop. For the first time, the workshop took place in Scandinavia and was hosted by Lisbeth Tranebjaerg and Herbert Lubs. For most participants this Workshop, held at the northernmost university in the world, presented a unique opportunity to visit this exotic place. Between sessions, the participants had a chance to experience 24 hours of daylight, codfishing, and extreme weather situations with excessive amounts of rain as well as spectacular changes in the light and rainbows. The format of the Workshop was a combination of platform presentations and poster presentations. In contrast to previous meetings, the Workshop opened with syndromal and non-syndromal X-linked mental retardation in order to allow time for discussion. 34 refs., 1 fig.

  16. X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.

    PubMed

    Brancaleoni, V; Balwani, M; Granata, F; Graziadei, G; Missineo, P; Fiorentino, V; Fustinoni, S; Cappellini, M D; Naik, H; Desnick, R J; Di Pierro, E

    2016-01-01

    X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromosomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP.

  17. Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28.

    PubMed

    Melamud, A; Shen, G-Q; Chung, D; Xi, Q; Simpson, E; Li, L; Peachey, N S; Zegarra, H; Hagstrom, S A; Wang, Q K; Traboulsi, E I

    2006-06-01

    We have defined a new genetic locus for an X linked form of retinitis pigmentosa (RP) on chromosome Xq28. We examined 15 members of a family in which RP appeared to be transmitted in an X linked manner. Ocular examinations were performed, and fundus photographs and electroretinograms were obtained for selected patients. Blood samples were obtained from all patients and an additional seven family members who were not given examinations. Visual acuity in four affected individuals ranged from 20/40 to 20/80+. Patients described the onset of night blindness and colour vision defects in the second decade of life, with the earliest at 13 years of age. Examined affected individuals had constricted visual fields and retinal findings compatible with RP. Based on full field electroretinography, cone function was more severely reduced than rod function. Female carriers had no ocular signs or symptoms and slightly reduced cone electroretinographic responses. Affected and non-affected family members were genotyped for 20 polymorphic markers on the X-chromosome spaced at 10 cM intervals. Genotyping data were analysed using GeneMapper software. Genotyping and linkage analyses identified significant linkage to markers DXS8061, DXS1073, and DXS1108 with two point LOD scores of 2.06, 2.17, and 2.20, respectively. Haplotype analysis revealed segregation of the disease phenotype with markers at Xq28. PMID:16740911

  18. X-linked intellectual disability related genes disrupted by balanced X-autosome translocations.

    PubMed

    Moysés-Oliveira, Mariana; Guilherme, Roberta Santos; Meloni, Vera Ayres; Di Battista, Adriana; de Mello, Claudia Berlim; Bragagnolo, Silvia; Moretti-Ferreira, Danilo; Kosyakova, Nadezda; Liehr, Thomas; Carvalheira, Gianna Maria; Melaragno, Maria Isabel

    2015-12-01

    Detailed molecular characterization of chromosomal rearrangements involving X-chromosome has been a key strategy in identifying X-linked intellectual disability-causing genes. We fine-mapped the breakpoints in four women with balanced X-autosome translocations and variable phenotypes, in order to investigate the corresponding genetic contribution to intellectual disability. We addressed the impact of the gene interruptions in transcription and discussed the consequences of their functional impairment in neurodevelopment. Three patients presented with cognitive impairment, reinforcing the association between the disrupted genes (TSPAN7-MRX58, KIAA2022-MRX98, and IL1RAPL1-MRX21/34) and intellectual disability. While gene expression analysis showed absence of TSPAN7 and KIAA2022 expression in the patients, the unexpected expression of IL1RAPL1 suggested a fusion transcript ZNF611-IL1RAPL1 under the control of the ZNF611 promoter, gene disrupted at the autosomal breakpoint. The X-chromosomal breakpoint definition in the fourth patient, a woman with normal intellectual abilities, revealed disruption of the ZDHHC15 gene (MRX91). The expression assays did not detect ZDHHC15 gene expression in the patient, thus questioning its involvement in intellectual disability. Revealing the disruption of an X-linked intellectual disability-related gene in patients with balanced X-autosome translocation is a useful tool for a better characterization of critical genes in neurodevelopment. © 2015 Wiley Periodicals, Inc. PMID:26290131

  19. New X linked spondyloepimetaphyseal dysplasia: report on eight affected males in the same family.

    PubMed Central

    Camera, G; Stella, G; Camera, A

    1994-01-01

    We report on a probably new form of spondyloepimetaphyseal dysplasia (SEMD) with an X linked inheritance pattern. Eight males were affected in the same family. We were able to examine three adult patients and we studied the skeletal radiological aspect of one of these patients at 2 years 6 months and at 9 years of age. The main clinical features are severe short trunked dwarfism, brachydactyly, normal facies, and normal intelligence. Radiologically, the diaphyses of all the long bones are short and broad. The epiphyses of the distal portion of the femora and those of the proximal and distal portions of the tibia are embedded in their metaphyses and there is marked narrowing of the intercondylar groove. There is moderate platyspondyly. Several vertebrae show an anterior tongue in infancy and severe irregularities of the upper and lower surfaces are present in adulthood. The 11th or 12th thoracic vertebra is wedge shaped. The pelvis is narrow. The distal ulnae and fibulae are disproportionately long. The hands show radial deviation and brachydactyly is present in the hands and feet. This X linked SEMD was not detectable at birth. Images PMID:8064814

  20. Linkage localization of X-linked Charcot-Marie-Tooth disease

    SciTech Connect

    Bergoffen, J. Univ. of Pennsylvania, Philadelphia ); Trofatter, J.; Haines, J.L. ); Pericak-Vance, M.A. ); Chance, P.F. ); Fischbeck, K.H. )

    1993-02-01

    Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.

  1. The X-linked F cell production locus: Genetic mapping and role in fetal hemoglobin production

    SciTech Connect

    Chang, Y.C.; Smith, K.D.; Moore, R.D.

    1994-09-01

    Postnatal fetal hemoglobin (Hb F) production is confined to a subset of erythocytes termed F-cells. There is a 10-20 fold variation in F-cell production in sickle cell disease (SCD) and normal individuals. Most of the variation in F-cell production has been attributed to a diallelic (High, Low) X-linked gene, the F-cell production (FCP) locus that we recently mapped to Xp22.2-22.3 (LOD=4.56, theta=0.04). Using multiple regression analysis in 262 Jamaican SCD patients we determined the relative contribution of the FCP locus and other variables previously associated with variation in Hb F level (gender, age, beta-globin haplotypes, number of alpha-globin genes and the FCP locus phenotypes). When the FCP locus is in the regression model, the FCP locus alone accounts for approximately 40% of the variation in Hb F level while the contribution of age, alpha-globin gene number, and beta-globin haplotypes was insignificant. When individuals with High FCP allele are removed from the analysis, the beta globin haplotype now contribute to >10% of the Hb F variation. We conclude that the X-linked FCP locus is the major determinant of all known variables in Hb F production. Using 4 highly polymorphic dinucleotide repeat markers that we identified from cosmids in Xp22.2-22.3, have localized the FCP locus to a 1 Mb minimal candidate region between DXS143 and DXS410.

  2. GPR143 Gene Mutations in Five Chinese Families with X-linked Congenital Nystagmus.

    PubMed

    Han, Ruifang; Wang, Xiaojuan; Wang, Dongjie; Wang, Liming; Yuan, Zhongfang; Ying, Ming; Li, Ningdong

    2015-01-01

    The ocular albinism type I (OA1) is clinically characterized by impaired visual acuity, nystagmus, iris hypopigmentation with translucency, albinotic fundus, and macular hypoplasia together with normally pigmented skin and hair. However, it is easily misdiagnosed as congenital idiopathic nystagmus in some Chinese patients with OA1 caused by the G-protein coupled receptor 143 (GPR143) gene mutations. Mutations in the FERM domain-containing 7 (FRMD7) gene are responsible for the X-linked congenital idiopathic nystagmus. In this study, five Chinese families initially diagnosed as X-linked congenital nystagmus were recruited and patients underwent ophthalmological examinations. After direct sequencing of the FRMD7 and GPR143 genes, five mutations in GPR143 gene were detected in each of the five families, including a novel nonsense mutation of c.333G>A (p.W111X), two novel splicing mutations of c.360+1G>C and c.659-1G>A, a novel small deletion mutation of c.43_50dupGACGCAGC (p.L20PfsX25), and a previously reported missense mutation of c.703G>A (p.E235K). Optical coherence tomography (OCT) examination showed foveal hypoplasia in all the affected patients with nystagmus. Our study further expands the GPR143 mutation spectrum and contributes to the study of GPR143 molecular pathogenesis. Molecular diagnosis and optical coherence tomography (OCT) are two useful tools for differential diagnosis. PMID:26160353

  3. Refined mapping of X-linked reticulate pigmentary disorder and sequencing of candidate genes

    PubMed Central

    2009-01-01

    X-linked reticulate pigmentary disorder with systemic manifestations in males (PDR) is very rare. Affected males are characterized by cutaneous and visceral symptoms suggestive of abnormally regulated inXammation. A genetic linkage study of a large Canadian kindred previously mapped the PDR gene to a greater than 40 Mb interval of Xp22–p21. The aim of this study was to identify the causative gene for PDR. The Canadian pedigree was expanded and additional PDR families recruited. Genetic linkage was performed using newer microsatellite markers. Positional and functional candidate genes were screened by PCR and sequencing of coding exons in affected males. The location of the PDR gene was narrowed to a ~4.9 Mb interval of Xp22.11–p21.3 between markers DXS1052 and DXS1061. All annotated coding exons within this interval were sequenced in one affected male from each of the three multiplex families as well as one singleton, but no causative mutation was identiWed. Sequencing of other X-linked genes outside of the linked interval also failed to identify the cause of PDR but revealed a novel nonsynonymous cSNP in the GRPR gene in the Maltese population. PDR is most likely due to a mutation within the linked interval not affecting currently annotated coding exons. PMID:18404279

  4. GPR143 Gene Mutations in Five Chinese Families with X-linked Congenital Nystagmus

    PubMed Central

    Han, Ruifang; Wang, Xiaojuan; Wang, Dongjie; Wang, Liming; Yuan, Zhongfang; Ying, Ming; Li, Ningdong

    2015-01-01

    The ocular albinism type I (OA1) is clinically characterized by impaired visual acuity, nystagmus, iris hypopigmentation with translucency, albinotic fundus, and macular hypoplasia together with normally pigmented skin and hair. However, it is easily misdiagnosed as congenital idiopathic nystagmus in some Chinese patients with OA1 caused by the G-protein coupled receptor 143 (GPR143) gene mutations. Mutations in the FERM domain–containing 7 (FRMD7) gene are responsible for the X-linked congenital idiopathic nystagmus. In this study, five Chinese families initially diagnosed as X-linked congenital nystagmus were recruited and patients underwent ophthalmological examinations. After direct sequencing of the FRMD7 and GPR143 genes, five mutations in GPR143 gene were detected in each of the five families, including a novel nonsense mutation of c.333G>A (p.W111X), two novel splicing mutations of c.360+1G>C and c.659-1G>A, a novel small deletion mutation of c.43_50dupGACGCAGC (p.L20PfsX25), and a previously reported missense mutation of c.703G>A (p.E235K). Optical coherence tomography (OCT) examination showed foveal hypoplasia in all the affected patients with nystagmus. Our study further expands the GPR143 mutation spectrum and contributes to the study of GPR143 molecular pathogenesis. Molecular diagnosis and optical coherence tomography (OCT) are two useful tools for differential diagnosis. PMID:26160353

  5. A three-year-old boy with X-linked adrenoleukodystrophy and congenital pulmonary adenomatoid malformation: a case report

    PubMed Central

    2009-01-01

    Introduction X-linked adrenoleukodystrophy leads to demyelination of the nervous system, adrenal insufficiency, and accumulation of long-chain fatty acids. Most young patients with X-linked adrenoleukodystrophy develop seizures and progressive neurologic deficits, and die within the first two decades of life. Congenital or acquired disorders of the respiratory system have not been previously described in patients with X-linked adrenoleukodystrophy. Case presentation A 3-year-old Arabic boy from Yemen presented with discoloration of the mucous membranes and nail beds, which were considered cyanoses due to methemoglobinemia. He also had shortness of breath, fatigue, emesis and dehydration episodes for which he was admitted to our hospital. Chest radiograph and chest computed tomography scans showed congenital pulmonary adenomatoid malformation. A few weeks before the removal of the malformation, he had a significant episode of hypotension and hypoglycemia. This development required further in-hospital evaluation that led to the diagnosis of adrenal insufficiency and the initiation of treatment with corticosteroids. One year later, he developed seizures and loss of consciousness. Magnetic resonance imaging of his head showed diffuse demyelination secondary to X-linked adrenoleukodystrophy. He was treated with anti-seizure and anti-oxidants, and was referred for bone marrow transplant evaluation. Conclusion The presence of adrenal insufficiency, neurologic deficits and seizures are common manifestations of X-linked adrenoleukodystrophy. The association of congenital lung disease with X-linked adrenoleukodystrophy or Addison's disease has not been described previously. PMID:20090870

  6. Canine hearing loss management.

    PubMed

    Scheifele, Lesa; Clark, John Greer; Scheifele, Peter M

    2012-11-01

    Dog owners and handlers are naturally concerned when suspicion of hearing loss arises for their dogs. Questions frequently asked of the veterinarian center on warning signs of canine hearing loss and what can be done for the dog if hearing loss is confirmed. This article addresses warning signs of canine hearing loss, communication training and safety awareness issues, and the feasibility of hearing aid amplification for dogs.

  7. Regulatory divergence of X-linked genes and hybrid male sterility in mice.

    PubMed

    Oka, Ayako; Shiroishi, Toshihiko

    2014-01-01

    Postzygotic reproductive isolation is the reduction of fertility or viability in hybrids between genetically diverged populations. One example of reproductive isolation, hybrid male sterility, may be caused by genetic incompatibility between diverged genetic factors in two distinct populations. Genetic factors involved in hybrid male sterility are disproportionately located on the X chromosome. Recent studies showing the evolutionary divergence in gene regulatory networks or epigenetic effects suggest that the genetic incompatibilities occur at much broader levels than had previously been thought (e.g., incompatibility of protein-protein interactions). The latest studies suggest that evolutionary divergence of transcriptional regulation causes genetic incompatibilities in hybrid animals, and that such incompatibilities preferentially involve X-linked genes. In this review, we focus on recent progress in understanding hybrid sterility in mice, including our studies, and we discuss the evolutionary significance of regulatory divergence for speciation.

  8. A Review of X-linked Charcot-Marie-Tooth Disease.

    PubMed

    Wang, Ying; Yin, Fei

    2016-05-01

    X-linked Charcot-Marie-Tooth disease (CMTX) is the second common genetic variant of CMT. CMTX type 1 causes 90% of CMTX. The most important clinical features of CMTX are similar with other types of CMT; however, a few patients get the central nervous system involved with or without white matter lesions; males are more severely and earlier affected than females. In this review, the authors focus on the origin and classification of CMTX, the central nervous system manifestations of CMTX1, the possible mechanism by which GJB1 mutations cause CMT1X, and the emerging therapeutic strategies for CMTX. Moreover, several cases are presented to illustrate the central nervous system manifestations.

  9. Arch fingerprints, hypotonia, and areflexia associated with X linked mental retardation.

    PubMed

    Stevenson, R E; Häne, B; Arena, J F; May, M; Lawrence, L; Lubs, H A; Schwartz, C E

    1997-06-01

    A syndrome with distinctive facies, poor muscle tone, absent deep tendon reflexes, tapered fingers, excessive fingerprint arches, genu valgum and mild-moderate mental retardation has occurred in four males in two generations of a white family of European ancestry. The facies are characterised by square configuration, tented upper lip, and thickening of the helices, upper eyelids, and alae nasi. At birth and at maturity, growth (head circumference, height, weight) of affected males is comparable to or greater than unaffected male sibs. Moderate impairment of cognitive function was documented (IQ scores between 40-51). Carriers show no heterozygote manifestations. This X linked condition appears to be different from other syndromes with mental retardation, although there are certain similarities with the alpha thalassaemia-mental retardation syndrome (ATR-X). Linkage analysis found tight linkage to DXS1166 and DXS995 in Xq13 and Xq21 respectively.

  10. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia

    SciTech Connect

    Allen, R.C.; Nachtman, R.G.; Belmont, J.W.; Rosenblatt, H.M.

    1994-01-01

    Bruton X-linked agammaglobulinemia (XLA) is a phenotypically recessive genetic disorder of B lymphocyte development. Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation. Skewing apparently results from defective growth and maturation of B cell precursors bearing a mutant active X chromosome. In this study, carrier status was tested in 58 women from 22 families referred with a history of agammaglobulinemia. Primary carrier analysis to examine patterns of X inactivation in CD19[sup +] peripheral blood cells (B lymphocytes) was conducted using quantitative PCR at the androgen-receptor locus. Obligate carriers of XLA demonstrated >95% skewing of X inactivation in peripheral blood CD19[sup +] cells but not in CD19[sup [minus

  11. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

    PubMed Central

    Lindert, Uschi; Cabral, Wayne A.; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M.; Yeetong, Patra; Weis, Maryann; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena N.; Janecke, Andreas R.; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R.; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C.; Shotelersuk, Vorasuk

    2016-01-01

    Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894

  12. Familial X-linked mental retardation and isolated growth hormone deficiency: Clinical and molecular findings

    SciTech Connect

    Hamel, B.C.J.; Smits, A.P.T.; Helm, B. van den

    1996-07-12

    We report on several members of a family with varying degrees of X-linked mental retardation (XLMR), isolated growth hormone deficiency (IGHD), and infantile behavior but without other consistent phenotypic abnormalities. Male patients continued to grow until well into their twenties and reached a height ranging from 135 to 159 cm. Except one, all female carriers were mentally normal; their adult height ranged from 159 to 168 cm. By linkage studies we have assigned the underlying genetic defect to the Xq24-q27.3 region, with a maximum lod score of Z = 3.26 at {theta} = 0.0 for the DXS294 locus. The XLMR-IGHD phenotype in these patients may be due to pleiotropic effects of a single gene or it may represent a contiguous gene syndrome. 18 refs., 6 figs., 3 tabs.

  13. "Lorenzo's oil" therapy for X-linked adrenoleukodystrophy: rationale and current assessment of efficacy.

    PubMed

    Moser, Hugo W; Moser, Ann B; Hollandsworth, Kim; Brereton, N Hong; Raymond, Gerald V

    2007-09-01

    X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder that damages the nervous system and is associated with the accumulation of saturated very long chain fatty acids (SVLCFA). Oral administration of "Lorenzo's oil" (LO), a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, normalizes the SVLCFA levels in plasma, but its clinical efficacy and the clinical indications for its use have been controversial for more than 15 years. We review the biochemical effects of LO administration and the rationale for its use and present a current appraisal of its capacity to reduce the risk for the childhood cerebral phenotype when administered to asymptomatic boys and to slow progression of adrenomyeloneuropathy in patients without cerebral involvement. We also present current efforts to provide definitive evaluation of its clinical efficacy and discuss its possible role in the new therapeutic opportunities that will arise if newborn screening for X-ALD is validated and implemented.

  14. Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency

    PubMed Central

    Chinen, Javier; Davis, Joie; De Ravin, Suk See; Hay, Beverly N.; Hsu, Amy P.; Linton, Gilda F.; Naumann, Nora; Nomicos, Effie Y. H.; Silvin, Christopher; Ulrick, Jean; Whiting-Theobald, Narda L.; Puck, Jennifer M.

    2007-01-01

    Retroviral gene therapy can restore immunity to infants with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (γc) of receptors for interleukins 2 (IL-2), −4, −7, −9, −15, and −21. We investigated the safety and efficacy of gene therapy as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant from a parent. Subjects received retrovirus-transduced autologous peripherally mobilized CD34+ hematopoietic cells. T-cell function significantly improved in the youngest subject (age 10 years), and multilineage retroviral marking occurred in all 3 children. PMID:17369490

  15. Zebrafish model for the genetic basis of X-linked retinitis pigmentosa.

    PubMed

    Raghupathy, Rakesh Kotapati; McCulloch, Daphne L; Akhtar, Saeed; Al-mubrad, Turki M; Shu, Xinhua

    2013-03-01

    Retinitis pigmentosa (RP) affects 1/4000 individuals in most populations, and X-linked RP (XLRP) is one of the most severe forms of human retinal degeneration. Mutations in both the retinitis pigmentosa GTPase regulator (RPGR) gene and retinitis pigmentosa 2 (RP2) gene account for almost all cases of XLRP. The functional roles of both RPGR and RP2 in the pathogenesis of XLRP are unclear. Due to the surprisingly high degree of functional conservation between human genes and their zebrafish orthologues, the zebrafish has become an important model for human retinal disorders. In this brief review, we summarize the functional characterization of XLRP-causing genes, RPGR and RP2, in zebrafish, and highlight recent studies that provide insight into the cellular functions of both genes. This will not only shed light on disease mechanisms in XLRP but will also provide a solid platform to test RP-causing mutants before proposing XLRP gene therapy trials.

  16. Assessing interethnic admixture using an X-linked insertion-deletion multiplex.

    PubMed

    Ribeiro-Rodrigues, Elzemar Martins; dos Santos, Ney Pereira Carneiro; dos Santos, Andrea Kely Campos Ribeiro; Pereira, Rui; Amorim, António; Gusmão, Leonor; Zago, Marco Antonio; dos Santos, Sidney Emanuel Batista

    2009-01-01

    In this study, a PCR multiplex was optimized, allowing the simultaneous analysis of 13 X-chromosome Insertion/deletion polymorphisms (INDELs). Genetic variation observed in Africans, Europeans, and Native Americans reveals high inter-population variability. The estimated proportions of X-chromosomes in an admixed population from the Brazilian Amazon region show a predominant Amerindian contribution (approximately 41%), followed by European (approximately 32%) and African (approximately 27%) contributions. The proportion of Amerindian contribution based on X-linked data is similar to the expected value based on mtDNA and Y-chromosome information. The accuracy for assessing interethnic admixture, and the high differentiation between African, European, and Native American populations, demonstrates the suitability of this INDEL set to measure ancestry proportions in three-hybrid populations, as it is the case of Latin American populations.

  17. Refining the genetic location of the gene for X linked hydrocephalus within Xq28.

    PubMed Central

    Jouet, M; Feldman, E; Yates, J; Donnai, D; Paterson, J; Siggers, D; Kenwrick, S

    1993-01-01

    The most common inherited form of hydrocephalus, X linked hydrocephalus (HSAS), is characterised by mental retardation, adducted thumbs, and spastic paraplegia. Genetic analysis has mapped the locus for HSAS to subchromosomal band Xq28 within a region of approximately 2 megabases of DNA. In order to refine the location of the disease gene we have conducted genetic linkage analysis with Xq28 marker loci in four additional HSAS families. A lod score of 4.26 with polymorphic marker DXS52 (St14) confirms the linkage of HSAS to Xq28. Identification of a recombination event between the HSAS gene and Xq28 loci F8C and DXS605 (2-19) reduces the size of the interval likely to contain the disease locus to about 1.5 megabases, the distance between DXS605 and DXS52. The locus for neural cell adhesion molecule, L1CAM, maps within this interval and therefore represents a candidate gene for HSAS. PMID:8474107

  18. A new form of X-linked mental retardation with growth retardation, deafness, and microgenitalism.

    PubMed Central

    Juberg, R C; Marsidi, I

    1980-01-01

    The proband and two maternal uncles were similarly affected by a unique constellation of mental retardation and physical abnormalities. There were severe retardation, growth less than the third percentile, and significantly delayed bone age. They manifested deafness, a flat nasal bridge, several ocular abnormalities, and a rudimentary scrotum with cryptorchidism, and one had a small penis. The proband also had onychodystrophy of his fingers and toes. Their birth weights and lengths were less than expected. No chromosomal or biochemical abnormality was detected. Both uncles died, but the proband is healthy at 4 years. Their phenotype is distinguished from other forms of X-linked mental retardation and appears to be a new syndrome. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:6107045

  19. X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment.

    PubMed

    Dibbens, Leanne M; Tarpey, Patrick S; Hynes, Kim; Bayly, Marta A; Scheffer, Ingrid E; Smith, Raffaella; Bomar, Jamee; Sutton, Edwina; Vandeleur, Lucianne; Shoubridge, Cheryl; Edkins, Sarah; Turner, Samantha J; Stevens, Claire; O'Meara, Sarah; Tofts, Calli; Barthorpe, Syd; Buck, Gemma; Cole, Jennifer; Halliday, Kelly; Jones, David; Lee, Rebecca; Madison, Mark; Mironenko, Tatiana; Varian, Jennifer; West, Sofie; Widaa, Sara; Wray, Paul; Teague, John; Dicks, Ed; Butler, Adam; Menzies, Andrew; Jenkinson, Andrew; Shepherd, Rebecca; Gusella, James F; Afawi, Zaid; Mazarib, Aziz; Neufeld, Miriam Y; Kivity, Sara; Lev, Dorit; Lerman-Sagie, Tally; Korczyn, Amos D; Derry, Christopher P; Sutherland, Grant R; Friend, Kathryn; Shaw, Marie; Corbett, Mark; Kim, Hyung-Goo; Geschwind, Daniel H; Thomas, Paul; Haan, Eric; Ryan, Stephen; McKee, Shane; Berkovic, Samuel F; Futreal, P Andrew; Stratton, Michael R; Mulley, John C; Gécz, Jozef

    2008-06-01

    Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

  20. X-linked agammaglobulinemia associated with B-precursor acute lymphoblastic leukemia.

    PubMed

    Hoshino, Akihiro; Okuno, Yusuke; Migita, Masahiro; Ban, Hideki; Yang, Xi; Kiyokawa, Nobutaka; Adachi, Yuichi; Kojima, Seiji; Ohara, Osamu; Kanegane, Hirokazu

    2015-02-01

    X-linked agammaglobulinemia (XLA) is clinically characterized by reduced number of peripheral B cells and diminished levels of serum immunoglobulins, and caused by a mutation in the Bruton's tyrosine kinase (BTK) gene, which play a pivotal role in signal transduction of pre-B-cell receptor (BCR) and BCR. B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in children, and it may be associated with gene alterations that regulate B-cell development. Here we described a first case of XLA associated BCP-ALL. The whole-exome sequencing revealed a somatic mutation in MLL2 in the sample from the onset of BCP-ALL. This study suggests that the alterations of BTK and MLL2 synergistically function as leukemogenesis. PMID:25591849

  1. X-linked agammaglobulinemia combined with juvenile idiopathic arthritis and invasive Klebsiella pneumoniae polyarticular septic arthritis.

    PubMed

    Zhu, Zaihua; Kang, Yuli; Lin, Zhenlang; Huang, Yanjing; Lv, Huoyang; Li, Yasong

    2015-02-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton's tyrosine kinase (BTK) gene. XLA can also present in combination with juvenile idiopathic arthritis (JIA), the major chronic rheumatologic disease in children. We report herein the first known case of a juvenile patient diagnosed with XLA combined with JIA that later developed into invasive Klebsiella pneumoniae polyarticular septic polyarthritis. An additional comprehensive review of XLA combined with JIA and invasive K. pneumoniae septic arthritis is also presented. XLA was identified by the detection of BTK mutations while the diagnosis of JIA was established by clinical and laboratory assessments. Septic arthritis caused by invasive K. pneumoniae was confirmed by culturing of the synovia and gene detection of the isolates. Invasive K. pneumoniae infections can not only result in liver abscesses but also septic arthritis, although this is rare. XLA combined with JIA may contribute to invasive K. pneumoniae infection.

  2. Membranous Glomerulopathy in an Adult Patient with X-Linked Agammaglobulinemia Receiving Intravenous Gammaglobulin

    PubMed Central

    Endo, LM; Giannobile, JV; Dobbs, AK; Foote, JB; Szymanska, E; Warnock, DG; Cook, WJ; Conley, ME; Schroeder, HW

    2013-01-01

    Background Immune complex deposition in the subepithelial zone of glomerular capillaries can lead to membranous glomerulopathy. Objective To present the case of a 23-year-old man with X-linked agammaglobulinemia (XLA) who developed idiopathic membranous glomerulopathy while receiving intravenous immunoglobulin (IVIG). Methods We performed an immunological workup, genetic testing, and a renal biopsy. Results XLA was confirmed with less than 0.02% CD19+ cells in the blood after sequence analysis revealed a nonfunctional BTK gene. He presented with microhematuria, which persisted for 3 years and spanned treatment with 5 different preparations of intravenous gammaglobulin. Immunohistochemistry revealed membranous glomerulopathy. Conclusion Although endogenous serum immunoglobulin (Ig) production is severely impaired in XLA, rare B lymphocytes that have managed to mature can produce functional IgG antibodies. The pathogenic immune complexes could reflect IVIG reacting with polymorphic autoantigens, an endogenous IgG-producing clone reacting with a common idiotype present in the IVIG, or both. PMID:21905506

  3. Identification of a novel mutation of the EDA gene in X-linked hypohidrotic ectodermal dysplasia.

    PubMed

    Xue, J J; Tan, B; Gao, Q P; Zhu, G S; Liang, D S; Wu, L Q

    2015-01-01

    This study aimed to identify the disease-causing mutation in the ectodysplasin A (EDA) gene in a Chinese family affected by X-linked hypohidrotic ectodermal dysplasia (XLHED). A family clinically diagnosed with XLHED was investigated. For mutation analysis, the coding region of EDA of 2 patients and 7 unaffected members of the family was sequenced. The detected mutation in EDA was investigated in 120 normal controls. A missense mutation (c.878T>G) in EDA was detected in 2 patients and 3 female carriers, but not in 4 unaffected members of the family. The mutation was not found in the 120 healthy controls and has not been reported previously. Our findings indicate that a novel mutation (c.878T>G) of EDA is associated with XLHED and adds to the repertoire of EDA mutations.

  4. Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene.

    PubMed Central

    Pinard, J M; Motte, J; Chiron, C; Brian, R; Andermann, E; Dulac, O

    1994-01-01

    Neuronal migration disorders can now be recognised by MRI. This paper reports two families in which the mothers had subcortical laminar heterotopia and four of their children had either similar heterotopia (two girls) or severe pachygyria or lissencephaly (two boys). Laminar heterotopia was more evident on MRI T2 weighted images. The patients had mild to severe epilepsy and mental retardation depending on the extent of cortical abnormalities. In these families, subcortical laminar heterotopia, pachygyria, and lissencephaly seem to share the same X linked or autosomal dominant gene. No chromosomal abnormalities, especially of chromosome 17, could be identified. For appropriate genetic counselling of the family of a child with lissencephaly or subcortical laminar heterotopia, MRI should be performed in parents or siblings with mental retardation or epilepsy. Images PMID:8057113

  5. Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies

    PubMed Central

    Ponader, Sabine; Burger, Jan A.

    2014-01-01

    Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy. PMID:24778403

  6. A Novel X-linked 4-Repeat Tauopathy with Parkinsonism and Spasticity

    PubMed Central

    Poorkaj, P.; Raskind, W.H.; Leverenz, J.B.; Matsushita, M.; Zabetian, C.P.; Samii, A.; Kim, S.; Gazi, N.; Nutt, J.G.; Wolff, J.; Yearout, D.; Greenup, J.L.; Steinbart, E.J.; Bird, T.D.

    2011-01-01

    The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson’s disease (PD), additional PD loci are likely to exist. We recently identified a multi-generational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant 4-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an approximately 20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and 4-repeat tau pathology, and defined a novel candidate gene locus spanning approximately 28 Mb from Xp11.2-Xq13.3. PMID:20629132

  7. Origins and antiquity of X-linked triallelic color vision systems in New World monkeys.

    PubMed

    Boissinot, S; Tan, Y; Shyue, S K; Schneider, H; Sampaio, I; Neiswanger, K; Hewett-Emmett, D; Li, W H

    1998-11-10

    It is known that the squirrel monkey, marmoset, and other related New World (NW) monkeys possess three high-frequency alleles at the single X-linked photopigment locus, and that the spectral sensitivity peaks of these alleles are within those delimited by the human red and green pigment genes. The three alleles in the squirrel monkey and marmoset have been sequenced previously. In this study, the three alleles were found and sequenced in the saki monkey, capuchin, and tamarin. Although the capuchin and tamarin belong to the same family as the squirrel monkey and marmoset, the saki monkey belongs to a different family and is one of the species that is most divergent from the squirrel monkey and marmoset, suggesting the presence of the triallelic system in many NW monkeys. The nucleotide sequences of these alleles from the five species studied indicate that gene conversion occurs frequently and has partially or completely homogenized intronic and exonic regions of the alleles in each species, making it appear that a triallelic system arose independently in each of the five species studied. Nevertheless, a detailed analysis suggests that the triallelic system arose only once in the NW monkey lineage, from a middle wavelength (green) opsin gene, and that the amino acid differences at functionally critical sites among alleles have been maintained by natural selection in NW monkeys for >20 million years. Moreover, the two X-linked opsin genes of howler monkeys (a NW monkey genus) were evidently derived from the incorporation of a middle (green) and a long wavelength (red) allele into one chromosome; these two genes together with the (autosomal) blue opsin gene would immediately enable even a male monkey to have trichromatic vision. PMID:9811872

  8. Silencing of X-Linked MicroRNAs by Meiotic Sex Chromosome Inactivation.

    PubMed

    Royo, Hélène; Seitz, Hervé; ElInati, Elias; Peters, Antoine H F M; Stadler, Michael B; Turner, James M A

    2015-10-01

    During the pachytene stage of meiosis in male mammals, the X and Y chromosomes are transcriptionally silenced by Meiotic Sex Chromosome Inactivation (MSCI). MSCI is conserved in therian mammals and is essential for normal male fertility. Transcriptomics approaches have demonstrated that in mice, most or all protein-coding genes on the X chromosome are subject to MSCI. However, it is unclear whether X-linked non-coding RNAs behave in a similar manner. The X chromosome is enriched in microRNA (miRNA) genes, with many exhibiting testis-biased expression. Importantly, high expression levels of X-linked miRNAs (X-miRNAs) have been reported in pachytene spermatocytes, indicating that these genes may escape MSCI, and perhaps play a role in the XY-silencing process. Here we use RNA FISH to examine X-miRNA expression in the male germ line. We find that, like protein-coding X-genes, X-miRNAs are expressed prior to prophase I and are thereafter silenced during pachynema. X-miRNA silencing does not occur in mouse models with defective MSCI. Furthermore, X-miRNAs are expressed at pachynema when present as autosomally integrated transgenes. Thus, we conclude that silencing of X-miRNAs during pachynema in wild type males is MSCI-dependent. Importantly, misexpression of X-miRNAs during pachynema causes spermatogenic defects. We propose that MSCI represents a chromosomal mechanism by which X-miRNAs, and other potential X-encoded repressors, can be silenced, thereby regulating genes with critical late spermatogenic functions.

  9. Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS)

    PubMed Central

    Korvatska, Olena; Strand, Nicholas S.; Berndt, Jason D.; Strovas, Tim; Chen, Dong-Hui; Leverenz, James B.; Kiianitsa, Konstantin; Mata, Ignacio F.; Karakoc, Emre; Greenup, J. Lynne; Bonkowski, Emily; Chuang, Joseph; Moon, Randall T.; Eichler, Evan E.; Nickerson, Deborah A.; Zabetian, Cyrus P.; Kraemer, Brian C.; Bird, Thomas D.; Raskind, Wendy H.

    2013-01-01

    We report a novel gene for a parkinsonian disorder. X-linked parkinsonism with spasticity (XPDS) presents either as typical adult onset Parkinson's disease or earlier onset spasticity followed by parkinsonism. We previously mapped the XPDS gene to a 28 Mb region on Xp11.2–X13.3. Exome sequencing of one affected individual identified five rare variants in this region, of which none was missense, nonsense or frame shift. Using patient-derived cells, we tested the effect of these variants on expression/splicing of the relevant genes. A synonymous variant in ATP6AP2, c.345C>T (p.S115S), markedly increased exon 4 skipping, resulting in the overexpression of a minor splice isoform that produces a protein with internal deletion of 32 amino acids in up to 50% of the total pool, with concomitant reduction of isoforms containing exon 4. ATP6AP2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy, a pathway frequently affected in Parkinson's disease. Reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function, as seen with siRNA knockdown in HEK293 cells, and may ultimately be responsible for the pathology. Another synonymous mutation in the same exon, c.321C>T (p.D107D), has a similar molecular defect of exon inclusion and causes X-linked mental retardation Hedera type (MRXSH). Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations. PMID:23595882

  10. Expression of myotubularins in blood platelets: Characterization and potential diagnostic of X-linked myotubular myopathy.

    PubMed

    Mansour, Rana; Severin, Sonia; Xuereb, Jean-Marie; Gratacap, Marie-Pierre; Laporte, Jocelyn; Buj-Bello, Ana; Tronchère, Hélène; Payrastre, Bernard

    2016-07-29

    Phosphoinositides play a key role in the spatiotemporal control of central intracellular processes and several specific kinases and phosphatases regulating the level of these lipids are implicated in human diseases. Myotubularins are a family of 3-phosphatases acting specifically on phosphatidylinositol 3-monophosphate and phosphatidylinositol 3,5 bisphosphate. Members of this family are mutated in genetic diseases including myotubularin 1 (MTM1) and myotubularin-related protein 2 (MTMR2) which mutations are responsible of X-linked centronuclear myopathy and Charcot-Marie-Tooth neuropathy, respectively. Here we show that MTM1 is expressed in blood platelets and that hundred microliters of blood is sufficient to detect the protein by western blotting. Since the most severe cases of pathogenic mutations of MTM1 lead to loss of expression of the protein, we propose that a minimal amount of blood can allow a rapid diagnostic test of X-linked myotubular myopathy, which is currently based on histopathology of muscle biopsy and molecular genetic testing. In platelets, MTM1 is a highly active 3-phosphatase mainly associated to membranes and found on the dense granules and to a lesser extent on alpha-granules. However, deletion of MTM1 in mouse had no significant effect on platelet count and on platelet secretion and aggregation induced by thrombin or collagen stimulation. Potential compensation by other members of the myotubularin family is conceivable since MTMR2 was easily detectable by western blotting and the mRNA of several members of the family increased during in vitro differentiation of human megakaryocytes and MEG-01 cells. In conclusion, we show the presence of several myotubularins in platelets and propose that minimal amounts of blood can be used to develop a rapid diagnostic test for genetic pathologies linked to loss of expression of these phosphatases.

  11. An X-Linked Cobalamin Disorder Caused by Mutations in Transcriptional Coregulator HCFC1

    PubMed Central

    Yu, Hung-Chun; Sloan, Jennifer L.; Scharer, Gunter; Brebner, Alison; Quintana, Anita M.; Achilly, Nathan P.; Manoli, Irini; Coughlin, Curtis R.; Geiger, Elizabeth A.; Schneck, Una; Watkins, David; Suormala, Terttu; Van Hove, Johan L.K.; Fowler, Brian; Baumgartner, Matthias R.; Rosenblatt, David S.; Venditti, Charles P.; Shaikh, Tamim H.

    2013-01-01

    Derivatives of vitamin B12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine. The most common inborn error of cobalamin metabolism, combined methylmalonic acidemia and hyperhomocysteinemia, cblC type, is caused by mutations in MMACHC. However, several individuals with presumed cblC based on cellular and biochemical analysis do not have mutations in MMACHC. We used exome sequencing to identify the genetic basis of an X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia, designated cblX. A missense mutation in a global transcriptional coregulator, HCFC1, was identified in the index case. Additional male subjects were ascertained through two international diagnostic laboratories, and 13/17 had one of five distinct missense mutations affecting three highly conserved amino acids within the HCFC1 kelch domain. A common phenotype of severe neurological symptoms including intractable epilepsy and profound neurocognitive impairment, along with variable biochemical manifestations, was observed in all affected subjects compared to individuals with early-onset cblC. The severe reduction in MMACHC mRNA and protein within subject fibroblast lines suggested a role for HCFC1 in transcriptional regulation of MMACHC, which was further supported by the identification of consensus HCFC1 binding sites in MMACHC. Furthermore, siRNA-mediated knockdown of HCFC1 expression resulted in the coordinate downregulation of MMACHC mRNA. This X-linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype. PMID:24011988

  12. X-linked mental retardation: Linkage results in five unrelated families

    SciTech Connect

    Moraine, C.L.; Dessay, B.; Toutain, A.

    1994-09-01

    X-linked mental retardations are a very common cause of mental deficiency in males. Combined clinical and linkage studies in great families can help to distinguish between particular pathologies in this very heterogenous group. In five unrelated families, we have assigned the corresponding genes to Xp22.2-p21.2 for family 1, Xp21.2-p11.21 for family 2, Xp11.4-p11.23 for family 3, Xq12 for family 4, and Xq28.5-pter for family 5, respectively. Clinical features were characterized by severe hypotonia with seizures and distinctive facies (family 1), hypotonia and hypoactivity with severe mental deficiency but absence of neurological signs (family 2), neonatal hypotonia with poor sucking and moderate intrauterine growth retardation (family 3), severe neonatal hypotonia with visual impairment and profound mental deficiency and seizures (family 4), and non-specific moderate mental deficiency (family 5). These results confirm the frequent gene localizations in Xq28 and in the pericentromeric region. But more precise clinical description of so-called non-specific X-linked mental retardations is necessary (especially for the natural history of mental deficiency) with the intention to associate several families in a unique linkage study. However, the recent description of different clinical patterns in three families with mutation in the L1CAM gene suggests that allelism may be more frequent than expected, that the real number of X-L.M.R. genes could be less important than previously reported, and that testing of candidate genes by mRNA or genomic DNA studies appears as a necessary step.

  13. X-linked intellectual disability type Nascimento is a clinically distinct, probably underdiagnosed entity

    PubMed Central

    2013-01-01

    X-linked intellectual disability type Nascimento (MIM #300860), caused by mutations in UBE2A (MIM *312180), is characterized by craniofacial dysmorphism (synophrys, prominent supraorbital ridges, deep-set, almond-shaped eyes, depressed nasal bridge, prominent columella, hypoplastic alae nasi, and macrostomia), skin anomalies (hirsutism, myxedematous appearance, onychodystrophy), micropenis, moderate to severe intellectual disability (ID), motor delay, impaired/absent speech, and seizures. Hitherto only five familial point mutations and four different deletions including UBE2A have been reported in the literature. We present eight additional individuals from five families with UBE2A associated ID - three males from a consanguineous family, in whom we identified a small deletion of only 7.1 kb encompassing the first three exons of UBE2A, two related males with a UBE2A missense mutation in exon 4, a patient with a de novo nonsense mutation in exon 6, and two sporadic males with larger deletions including UBE2A. All affected male individuals share the typical clinical phenotype, all carrier females are unaffected and presented with a completely skewed X inactivation in blood. We conclude that 1.) X-linked intellectual disability type Nascimento is a clinically very distinct entity that might be underdiagnosed to date. 2.) So far, all females carrying a familial UBE2A aberration have a completely skewed X inactivation and are clinically unaffected. This should be taken in to account when counselling those families. 3.) The coverage of an array should be checked carefully prior to analysis since not all arrays have a sufficient resolution at specific loci, or alternative quantitative methods should be applied not to miss small deletions. PMID:24053514

  14. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes

    PubMed Central

    Hackett, Anna; Tarpey, Patrick S; Licata, Andrea; Cox, James; Whibley, Annabel; Boyle, Jackie; Rogers, Carolyn; Grigg, John; Partington, Michael; Stevenson, Roger E; Tolmie, John; Yates, John RW; Turner, Gillian; Wilson, Meredith; Futreal, Andrew P; Corbett, Mark; Shaw, Marie; Gecz, Jozef; Raymond, F Lucy; Stratton, Michael R; Schwartz, Charles E; Abidi, Fatima E

    2010-01-01

    Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported. PMID:20029458

  15. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.

    PubMed

    Hackett, Anna; Tarpey, Patrick S; Licata, Andrea; Cox, James; Whibley, Annabel; Boyle, Jackie; Rogers, Carolyn; Grigg, John; Partington, Michael; Stevenson, Roger E; Tolmie, John; Yates, John Rw; Turner, Gillian; Wilson, Meredith; Futreal, Andrew P; Corbett, Mark; Shaw, Marie; Gecz, Jozef; Raymond, F Lucy; Stratton, Michael R; Schwartz, Charles E; Abidi, Fatima E

    2010-05-01

    Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.

  16. The Role of Neuronal Complexes in Human X-Linked Brain Diseases

    PubMed Central

    Laumonnier, Frédéric ; Cuthbert, Peter C. ; Grant, Seth G. N. 

    2007-01-01

    Beyond finding individual genes that are involved in medical disorders, an important challenge is the integration of sets of disease genes with the complexities of basic biological processes. We examine this issue by focusing on neuronal multiprotein complexes and their components encoded on the human X chromosome. Multiprotein signaling complexes in the postsynaptic terminal of central nervous system synapses are essential for the induction of neuronal plasticity and cognitive processes in animals. The prototype complex is the N-methyl-d-aspartate receptor complex/membrane-associated guanylate kinase–associated signaling complex (NRC/MASC) comprising 185 proteins and embedded within the postsynaptic density (PSD), which is a set of complexes totaling ∼1,100 proteins. It is striking that 86% (6 of 7) of X-linked NRC/MASC genes and 49% (19 of 39) of X-chromosomal PSD genes are already known to be involved in human psychiatric disorders. Moreover, of the 69 known proteins mutated in X-linked mental retardation, 19 (28%) encode postsynaptic proteins. The high incidence of involvement in cognitive disorders is also found in mouse mutants and indicates that the complexes are functioning as integrated entities or molecular machines and that disruption of different components impairs their overall role in cognitive processes. We also noticed that NRC/MASC genes appear to be more strongly associated with mental retardation and autism spectrum disorders. We propose that systematic studies of PSD and NRC/MASC genes in mice and humans will give a high yield of novel genes important for human disease and new mechanistic insights into higher cognitive functions. PMID:17236127

  17. Is X-linked methyl-CpG binding protein 2 a new target for the treatment of Parkinson's disease

    PubMed Central

    Xie, Teng; Zhang, Jie; Yuan, Xianhou; Yang, Jing; Ding, Wei; Huang, Xin; Wu, Yong

    2013-01-01

    X-linked methyl-CpG binding protein 2 mutations can induce symptoms similar to those of Parkinson's disease and dopamine metabolism disorders, but the specific role of X-linked methyl-CpG binding protein 2 in the pathogenesis of Parkinson's disease remains unknown. In the present study, we used 6-hydroxydopamine-induced human neuroblastoma cell (SH-SY5Y cells) injury as a cell model of Parkinson's disease. The 6-hydroxydopamine (50 μmol/L) treatment decreased protein levels for both X-linked methyl-CpG binding protein 2 and tyrosine hydroxylase in these cells, and led to cell death. However, overexpression of X-linked methyl-CpG binding protein 2 was able to ameliorate the effects of 6-hydroxydopamine, it reduced 6-hydroxydopamine-induced apoptosis, and increased the levels of tyrosine hydroxylase in SH-SY5Y cells. These findings suggesting that X-linked methyl-CpG binding protein 2 may be a potential therapeutic target for the treatment of Parkinson's disease. PMID:25206503

  18. Arrested rearrangement of TCR V[beta] genes in thymocytes from children with x-linked severe combined immunodeficiency disease

    SciTech Connect

    Sleasman, J.W.; Harville, T.O.; White, G.B.; Barrett, D.J. ); George, J.F. ); Goodenow, M.M. Univ. of Alabama, Birmingham, AL )

    1994-07-01

    Human X-linked severe combined immunodeficiency disease (SCID) is an immunodeficiency disorder in which T cell development is arrested in the thymic cortex. B lymphocytes in children with X-linked SCID seem to differentiate normally. X-linked SCID is associated with a mutation in the gene that encodes the IL-2R [gamma]-chain. Because TCR-[beta] gene recombination is a pivotal initial event in T lymphocyte onteogeny within the thymus, the authors hypothesized that a failure to express normal IL-2R[gamma] could lead to impaired TCR-[beta] gene recombination in early thymic development. PCR was used to determine the status of TCR-[beta] gene-segment rearrangements in thymic DNA that had been obtained from children with X-linked SCID. The initial step in TCR-[beta] gene rearrangement, that of D[beta] to J[beta] recombination, was readily detected in all thymus samples from children with X-linked SCID; in contrast, V[beta] to DJ[beta] gene rearrangements were undetectable in the same samples. Both D[beta] to J[beta] and V[beta] to DJ[beta] TCR genes were rearranged in the thymic tissues obtained from immunologically normal children. The authors conclude that TCR[beta]-chain gene rearrangement is arrested in children with X-linked SCID. The results suggest a causative relationship between the failure of TCR [beta]-chain gene arrangements to proceed beyond DJ[beta] rearrangements and the production of a nonfunctional IL-2R [gamma]-chain. 45 refs., 3 figs.

  19. An X-linked homologue of the autosomal inprinted gene ZNF127 escapes X inactivation

    SciTech Connect

    Longstreet, M.; Nicholls, R.D.; Willard, H.F.

    1994-09-01

    The ZNF127 gene has been shown to be subject to parental imprinting in both humans and the mouse and maps to within the Prader-Willi/Angelman Syndrome critical region on chromosome 15. We have cloned two X-linked related loci, one of which, ZNFXp is a transcribed gene while the other, ZNFXq, is an untranscribed pseudogene. ZNFXp is 83.6% identical to ZNFXq and 65.4% identical to ZNF127 over 1.4 kb of open reading frame they share in common, Like ZNF127, the predicted protein sequence of ZNFXp contains a C{sub 3}HC{sub 4} zinc finger domain and C{sub 3}H zinc finger-like motifs. Whereas ZNF127 has three C{sub 3}H motifs, ZNFXp has four. A strong CpG island is located within 1 kb 5{prime} of the predicted amino terminus of ZNFXp. Expression of ZNFXp has been detected from mouse/human somatic cell hybrids containing either an active (n=2) or an inactive (n=4) chromosome, and thus escapes X inactivation. Probes made from the 3{prime} UTR of ZNFXp detect a number of related loci in both human and murine DNA, none of which is the ZNF127 locus on chromosome 15. None of the detectable murine bands shows dosage differences between males and females as would be expected for X-linked loci. This raises the possibility that ZNFXp inserted into the human X chromosome after its divergence from a common ancestor with the murine X. We have mapped ZNFXp to Xp11.4 by Southern blotting and PCR of hybrid DNAs and by fluorescence in situ hybridization (FISH). ZNFXq maps within the X Inactivation Center (XIC) region on Xq13.2, approximately 300 kb distal to the XIST gene. We find it intriguing, and perhaps significant, that two members of this gene family are subject to epigenetic regulation -- one autosomal imprinting, and the other escape from X inactivation. These results could imply an evolutionary and mechanistic relationship between these two processes.

  20. Mutations in the DLG3 Gene Cause Nonsyndromic X-Linked Mental Retardation

    PubMed Central

    Tarpey, Patrick; Parnau, Josep; Blow, Matthew; Woffendin, Hayley; Bignell, Graham; Cox, Charles; Cox, James; Davies, Helen; Edkins, Sarah; Holden, Simon; Korny, Angelique; Mallya, Uma; Moon, Jenny; O’Meara, Sarah; Parker, Adrian; Stephens, Philip; Stevens, Claire; Teague, Jon; Donnelly, Andrew; Mangelsdorf, Marie; Mulley, John; Partington, Michael; Turner, Gillian; Stevenson, Roger; Schwartz, Charles; Young, Ian; Easton, Douglas; Bobrow, Martin; Futreal, P. Andrew; Stratton, Michael R.; Gecz, Jozef; Wooster, Richard; Raymond, F. Lucy

    2004-01-01

    We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations. PMID:15185169

  1. Identification of novel Bruton's tyrosine kinase mutations in 10 unrelated subjects with X linked agammaglobulinaemia.

    PubMed Central

    Brooimans, R A; van den Berg, A J; Rijkers, G T; Sanders, L A; van Amstel, J K; Tilanus, M G; Grubben, M J; Zegers, B J

    1997-01-01

    Mutations of the Bruton's tyrosine kinase (Btk) gene cause X linked agammaglobulinaemia (XLA). This inherited immunodeficiency disease causes an arrest in B cell differentiation of pre-B cells to mature B cells. In this study we report the characterisation of mutations in the Btk gene in 10 unrelated XLA families. The screening approach we used was based on reverse transcriptase PCR and direct cycle sequencing of the amplified products followed by analysis of the observed mutations at the level of genomic DNA. The single strand confirmation polymorphism (SSCP) technique was used for assessment of the carriers in some of these families. Various mutations throughout the coding gene were observed, including missense and nonsense mutations, a deletion, and several splicing defects. None of the mutations except one has been previously described. There were three point mutations resulting in a single amino acid substitution. One of these missense mutations was observed in a conserved region of the PH domain, the other two were found in the src homology domain 2 that is involved in phosphotyrosyl peptide binding. Two mutations were single base pair substitutions resulting in premature stop codons. In four patients abnormal Btk transcripts were found that were the result of aberrant splicing. One small deletion was observed causing a frameshift and a secondary premature termination signal. Characterisation of the mutations responsible for XLA allowed us to diagnose the disease conclusively and identify the phenotypically normal female carriers. Images PMID:9192269

  2. Linkage mapping of a severe X-linked mental retardation syndrome

    SciTech Connect

    Malmgren, H.; Sundvall, M.; Steen-Bondeson, M.L.; Pettersson, U. ); Dahl, N. University Hospital, Uppsala ); Gustavson, K.H.; Anneren, G.; Wadelius, C. )

    1993-06-01

    A four-generation Swedish family with a new type of X-linked mental retardation syndrome was recently reported by Gustavson et al. The complex syndrome includes microcephaly, severe mental retardation, optical atrophy with decreased vision or blindness, severe hearing defect, characteristic facial features, spasticity, seizures, and restricted joint motility. The patients die during infancy or early in childhood. Twenty-one family members, including two affected males, were available for study. Linkage analysis was conducted in the family by using 11 RFLP markers and 10 VNTR markers spread along the X chromosome. A hypervariable short tandem repeat of DXS294 at Xq26 showed a peak two-point lod score of 3.35 at zero recombination fraction. Calculations using the same markers revealed a multipoint peak lod score of 3.65 at DXS294. Crossover events with the centromeric marker DXS424 and the telomeric marker DXS297 delimit a probable region for the gene localization. It is noteworthy that the disease loci of two other syndromes with overlapping clinical manifestations recently were shown by Turner et al. and Pettigrew et al. to be linked to markers at Xq26. 29 refs., 2 figs., 1 tab.

  3. Phenotypic variability in X-linked ocular albinism: Relationship to linkage genotypes

    SciTech Connect

    Schnur, R.E. |; Wick, P.A.; Bailey, C.; Rebbeck, T.; Weleber, R.G.; Wagstaff, J.; Grix, A.W.; Pagon, R.A.; Hockey, A.; Edwards, M.J.

    1994-09-01

    One hundred nineteen individuals from 11 families with X-linked ocular albinism (OA1) were studied with respect to both their clinical phenotypes and their linkage genotypes. In a four-generation Australian family, two affected males and an obligatory carrier lacked cutaneous melanin macroglobules (MMGs); ocular features were identical to those of Nettleship-Falls OA1. Four other families had more unusual phenotypic features in addition to OA1. All OA1 families were genotyped at DXS16, DXS85, DXS143, STS, and DXS452 and for a CA-repeat polymorphism at the Kallmann syndrome locus (KAL). Separate two-point linkage analyses were performed for the following: group A, six families with biopsy-proved MMGs in at least one affected male; group B, four families whose biopsy status was not known; and group C, OA-9 only (16 samples), the family without MMGs. At the set of loci closest to OA1, there is no clear evidence in our data set for locus heterogeneity between groups A and C or among the four other families with complex phenotypes. Combined multipoint analysis (LINKMAP) in the 11 families and analysis of individual recombination events confirms that the major locus for OA1 resides within the DXS85-DXS143 interval. The authors suggest that more detailed clinical evaluations of OA1 individuals and families should be performed for future correlation with specific mutations in candidate OA1 genes. 29 refs., 5 figs., 4 tabs.

  4. Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia

    PubMed Central

    Chen, Xia-Fang; Wang, Wei-Fan; Zhang, Yi-Dan; Zhao, Wei; Wu, Jing; Chen, Tong-Xin

    2016-01-01

    Abstract X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency. XLA patients typically present with very low numbers of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Most XLA patients carry mutations in Bruton tyrosine kinase (BTK) gene. The genetic background and clinical features of 174 Chinese patients with XLA were investigated. The relationship between specific BTK gene mutations and severity of clinical manifestations was also examined. Mutations were graded from mild to severe based on structural and functional prediction through bioinformatics analysis. One hundred twenty-seven mutations were identified in 142 patients from 124 families, including 45 novel mutations and 82 recurrent mutations that were distributed over the entire BTK gene sequence. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset. This report constitutes the largest group of patients with BTK mutations in China. A genotype–phenotype correlation was observed in this study. Early diagnosis of congenital agammaglobulinemia should be based on clinical symptoms, family history, and molecular analysis of the BTK gene. PMID:27512878

  5. Deep brain stimulation and dantrolene for secondary dystonia in x-linked adrenoleukodystrophy.

    PubMed

    van Karnebeek, Clara; Horvath, Gabriella; Murphy, Tyler; Purtzki, Jacqueline; Bowden, Kristin; Sirrs, Sandra; Honey, Christopher R; Stockler, Sylvia

    2015-01-01

    Deep brain stimulation (DBS) has been used to treat secondary dystonias caused by inborn errors of metabolism with varying degrees of effectiveness. Here we report for the first time the application of DBS as treatment for secondary dystonia in a 22-year-old male with X-linked adrenoleukodystrophy (X-ALD). The disease manifested at age 6 with ADHD, tics, and dystonic gait, and deteriorated to loss of ambulation by age 11, and speech difficulties, seizures, and characteristic adrenal insufficiency by age 16. DBS in the globus pallidus internus was commenced at age 18. However, after 25 months, no improvement in dystonia was observed (Burke-Fahn-Marsden (BFM) scores of 65.5 and 62 and disability scores of 28 and 26, pre- and post-DBS, respectively) and the DBS device was removed. Treatment with dantrolene reduced skeletal muscle tone and improved movement (Global Dystonia Rating Scores from 5 to 1 and BFM score 42). Therefore, we conclude that DBS was a safe but ineffective intervention in our case with long-standing dystonia, whereas treatment of spasticity with dantrolene did improve the movement disorder in this young man with X-ALD.

  6. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

    PubMed

    De Ravin, Suk See; Wu, Xiaolin; Moir, Susan; Anaya-O'Brien, Sandra; Kwatemaa, Nana; Littel, Patricia; Theobald, Narda; Choi, Uimook; Su, Ling; Marquesen, Martha; Hilligoss, Dianne; Lee, Janet; Buckner, Clarissa M; Zarember, Kol A; O'Connor, Geraldine; McVicar, Daniel; Kuhns, Douglas; Throm, Robert E; Zhou, Sheng; Notarangelo, Luigi D; Hanson, I Celine; Cowan, Mort J; Kang, Elizabeth; Hadigan, Coleen; Meagher, Michael; Gray, John T; Sorrentino, Brian P; Malech, Harry L

    2016-04-20

    X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1. PMID:27099176

  7. X-Linked Recessive form of Nephrogenic Diabetes Insipidus in a 7-Year-Old Boy.

    PubMed

    Janchevska, A; Tasic, V; Gucev, Z; Krstevska-Konstantinova, M; Cheong, H I

    2014-12-01

    Nephrogenic diabetes insipidus (NDI) is caused by the inability of renal collecting duct cells to respond to arginine vasopressin (AVP)/antidiuretic hormone (ADH). We present the case of a 7-year-old boy with a history of excretion of large amounts of dilute urine and polydipsia since infancy. The boy had several vomiting episodes with mild dehydration during the first 3 years of life. There was no evidence of headaches, dizziness or visual problems. He drinks between 2 and 3 L/day and has 24-hour diuresis of 2 liters, now. He has prepubertal appearance with appropriate weight [+0.85 standard deviation score (SDS)] and height (+0.15 SDS) for his age. His intelligence was also normal. The water deprivation test showed low urine osmolality after 8 hours of dehydration. After desmopressin administration, urine osmolality remained low. Serum osmolality was in the normal range for sex and age before and after desmopressin administration. This indicated a nephrogenic form of diabetes insipidus. Molecular analyses revealed a P286L [p.Pro(CCC)286Leu(CTC)] mutation in the AVPR2 gene, that was inherited from his mother. This patient is the first case with genetically confirmed X-linked inherited form of NDI in the Republic of Macedonia. Molecular analysis confirmed the clinical diagnosis and enabled genetic advice for this family. PMID:25937802

  8. X inactivation in females with X-linked Charcot–Marie–Tooth disease

    PubMed Central

    Murphy, Sinéad M.; Ovens, Richard; Polke, James; Siskind, Carly E.; Laurà, Matilde; Bull, Karen; Ramdharry, Gita; Houlden, Henry; Murphy, Raymond P.J.; Shy, Michael E.; Reilly, Mary M.

    2012-01-01

    X-linked Charcot–Marie–Tooth disease (CMT1X) is the second most common inherited neuropathy, caused by mutations in gap junction beta-1 (GJB1). Males have a uniformly moderately severe phenotype while females have a variable phenotype, suggested to be due to X inactivation. We aimed to assess X inactivation pattern in females with CMT1X and correlate this with phenotype using the CMT examination score to determine whether the X inactivation pattern accounted for the variable phenotype in females with CMT1X. We determined X inactivation pattern in 67 females with CMT1X and 24 controls using the androgen receptor assay. We were able to determine which X chromosome carried the GJB1 mutation in 30 females. There was no difference in X inactivation pattern between patients and controls. In addition, there was no correlation between X inactivation pattern in blood and phenotype. A possible explanation for these findings is that the X inactivation pattern in Schwann cells rather than in blood may explain the variable phenotype in females with CMT1X. PMID:22483671

  9. X inactivation in females with X-linked Charcot-Marie-Tooth disease.

    PubMed

    Murphy, Sinéad M; Ovens, Richard; Polke, James; Siskind, Carly E; Laurà, Matilde; Bull, Karen; Ramdharry, Gita; Houlden, Henry; Murphy, Raymond P J; Shy, Michael E; Reilly, Mary M

    2012-07-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common inherited neuropathy, caused by mutations in gap junction beta-1 (GJB1). Males have a uniformly moderately severe phenotype while females have a variable phenotype, suggested to be due to X inactivation. We aimed to assess X inactivation pattern in females with CMT1X and correlate this with phenotype using the CMT examination score to determine whether the X inactivation pattern accounted for the variable phenotype in females with CMT1X. We determined X inactivation pattern in 67 females with CMT1X and 24 controls using the androgen receptor assay. We were able to determine which X chromosome carried the GJB1 mutation in 30 females. There was no difference in X inactivation pattern between patients and controls. In addition, there was no correlation between X inactivation pattern in blood and phenotype. A possible explanation for these findings is that the X inactivation pattern in Schwann cells rather than in blood may explain the variable phenotype in females with CMT1X.

  10. {open_quotes}Unspecific{close_quotes} X-linked mental retardation: Clinical, genetic and molecular studies

    SciTech Connect

    Ropers, H.H.; Maacel, S. van der; Knoers, N.

    1994-09-01

    Previous linkage studies have assigned a gene for non-syndromic X-linked mental retardation (XMR) to at least 8 different regions on the X-chromosome. The fragile X-syndrome (FRAXA) does not account for more than 40% of all cases; in most XMR families early diagnosis and prevention is not possible. As part of a systematic study into {open_quotes}unspecific{close_quotes} XMR involving more than 30 non-FRAXA families, linkage studies have enabled us to map the respective genes in 4 families to the Xp11.4-q12 interval with peak lod scores around the ALAS2 locus. In three other families, the gene defect could be assigned to the KAL-DMD, DXS424-FRAXAC2 and DSX52-Xqter intervals, respectively. In one of these families, small stature due to growth hormone deficiency was observed as a distinctive clinical feature. Molecular cloning of the breakpoint in a mentally retarded girl with a balanced t(Xq13;13q) translocation has enabled us to isolate an X-chromosomal gene which is disrupted in this patient and is highly expressed in brain. YAC cloning strategies are being employed to clone another XMR gene, which has been identified previously in the vicinity of the CHM locus and genes involved in mentally retarded patients with two different inversions, inv(X)(q21p11) and inv(X)(p21q24), respectively.

  11. Detection and validation of copy number variation in X-linked mental retardation.

    PubMed

    Bauters, M; Weuts, A; Vandewalle, J; Nevelsteen, J; Marynen, P; Van Esch, H; Froyen, G

    2008-01-01

    Studies to identify the genetic defects associated with X-linked mental retardation (XLMR) in males have revealed tens of genes important for normal brain development and cognitive functioning in men. Despite extensive efforts in breakpoint cloning of chromosomal rearrangements and mutation screening of candidate genes on the X chromosome, still many XLMR families and sporadic cases remain unsolved. It is now clear that submicroscopic copy number changes on the X chromosome can explain about 5% of these idiopathic cases. Interestingly, beside gene deletions, an increase in gene dosage due to genomic duplications seems to contribute to causality more often than expected. Since larger duplications on the X chromosome are tolerated compared to deletions, they often harbour more than one gene hampering the identification of the causal gene. In contrast to copy number variations (CNVs) on autosomes, most disease-associated CNVs on the X chromosome in males are inherited from their mothers who normally do not present with any clinical symptoms due to non-random X inactivation. Here, we review the different methods applied to study copy number alterations on the X chromosome in patients with cognitive impairment, discuss those CNVs that are associated with disease and elaborate on the genes and mechanisms involved. At the end, we will resume in vivo assays to study the relation of CNVs on the X chromosome and mental disability.

  12. Four unrelated patients with Lubs X-linked mental retardation syndrome and different Xq28 duplications.

    PubMed

    Bartsch, Oliver; Gebauer, Konstanze; Lechno, Stanislav; van Esch, Hilde; Froyen, Guy; Bonin, Michael; Seidel, Jörg; Thamm-Mücke, Barbara; Horn, Denise; Klopocki, Eva; Hertzberg, Christoph; Zechner, Ulrich; Haaf, Thomas

    2010-02-01

    The Lubs X-linked mental retardation syndrome (MRXSL) is caused by small interstitial duplications at distal Xq28 including the MECP2 gene. Here we report on four novel male patients with MRXSL and different Xq28 duplications delineated by microarray-based chromosome analysis. All mothers were healthy carriers of the duplications. Consistent with an earlier report [Bauters et al. (2008); Genome Res 18: 847-858], the distal breakpoints of all four Xq28 duplications were located in regions containing low-copy repeats (LCRs; J, K, and L groups), which may facilitate chromosome breakage and reunion events. The proximal breakpoint regions did not contain known LCRs. Interestingly, we identified apparent recurrent breakage sites in the proximal and distal breakpoint regions. Two of the four patients displayed more complex rearrangements. Patient 2 was endowed with a quadruplicated segment and a small triplication within the duplication, whereas patient 3 displayed two triplicated segments within the duplication, supporting that the Fork Stalling and Template Switching (FoSTeS) model may explain a subset of the structural rearrangements in Xq28. Clinically, muscular hypertonia and contractures of large joints may present a major problem in children with MRXSL. Because injection of botulinum toxin (BT-A; Botox) proved to be extremely helpful for patient 1, we recommend consideration of Botox treatment in other patients with MRXSL and severe joint contractures.

  13. X chromosome array-CGH for the identification of novel X-linked mental retardation genes.

    PubMed

    Bauters, Marijke; Van Esch, Hilde; Marynen, Peter; Froyen, Guy

    2005-01-01

    Array-CGH technology for the detection of submicroscopic copy number changes in the genome has recently been developed for the identification of novel disease-associated genes. It has been estimated that submicroscopic genomic deletions or duplications will be present in 5-7% of patients with idiopathic mental retardation (MR). Since 30% more males than females are diagnosed with MR, we have developed a full coverage X chromosome array-CGH with a theoretical resolution of 82 kb, for the detection of copy number alterations in patients with suspected X-linked mental retardation (XLMR). First, we have validated the genomic location of X-derived clones through male versus female hybridisations. Next, we validated our array for efficient and reproducible detection of known alterations in XLMR patients. In all cases, we were able to detect the deletions and duplications in males as well as females. Due to the high resolution of our X-array, the boundaries of the genomic aberrations could clearly be identified making genotype-phenotype studies more reliable. Here, we describe the production and validation of a full coverage X-array-CGH, which will allow for fast and easy screening of submicroscopic copy number alterations in XLMR patients with the aim to identify novel MR genes or mechanisms involved in a deranged cognitive development.

  14. Accuracy of the clinical diagnosis of recessive X-linked ichthyosis vs ichthyosis vulgaris.

    PubMed

    Cuevas-Covarrubias, S A; Kofman-Alfaro, S H; Palencia, A B; Díaz-Zagoya, J C

    1996-09-01

    The present study analyzes the accuracy of the clinical diagnosis of X-linked ichthyosis (XLI) vs ichthyosis vulgaris (IV), in a sample of Mexican patients. The study was double blind, using steroid sulfatase (STS) activity as the golden standard. Twenty male patients were included; 16 corresponded to XLI and 4 to IV. The clinical diagnosis was correct in 9 of the 16 XLI cases (56%) and in 2 of the 4 IV cases (50%). Some clinical findings in XLI, such as cryptorchidism in patients and delayed labor in their mothers, were important features for diagnosis. Statistical analysis of the results showed: among physicians (n = 2) Kappa value 0.50, specific concordance 0.40, and absolute concordance 0.75; other values were sensibility 0.56, specificity 0.50, positive predictive value 0.82, negative predictive value 0.22, accuracy 0.55, prevalence 0.80. In conclusion, the differential diagnosis of XLI and IV is very difficult, and we consider that this is not explained either by personal skills or by other conditions. It could be attributed to the similarities in skin manifestations of these two diseases. The performance of the STS assay is imperative in order to correctly diagnose the disease and offer adequate genetic counseling.

  15. Icebox, a recessive X-linked mutation in Drosophila causing low sexual receptivity.

    PubMed

    Kerr, C; Ringo, J; Dowse, H; Johnson, E

    1997-11-01

    The X-linked recessive mutation icebox (ibx; 1-23, 7F1) of Drosophila melanogaster lowers the sexual receptivity of females. The probability of mating with mature wild-type males is reduced in ibx homozygotes, and the frequency of rejection behavior (rate per minute) towards courting males is increased. ibx fails to complement In(1)RA35, which is a lethal allele of Neuroglian (Nrg, which encodes a transmembrane protein found in embryonic tissues including the nervous system) due to a breakpoint in that gene; however, both l(1)B4 and l(1)VA142, other lethal mutations of Nrg, do complement ibx. 12-h ibx embryos exhibit a normal pattern of staining for the Neuroglian-specific antibody, Mab BP104. Males and females mutant for ibx have normal egg-to-adult survival and appear normal in several "general" behavioral traits including olfaction, phototaxis, locomotor activity, and heartbeat. ibx males court normally, and are successful in mating. These characteristics suggest that ibx does not cause sensory or motor defects. Ovarian growth and sperm storage are wild-type in ibx/ibx females. Treatment with the JH analog methoprene increases the receptivity of ibx/ibx females.

  16. Current and future pharmacological treatment strategies in X-linked adrenoleukodystrophy.

    PubMed

    Berger, Johannes; Pujol, Aurora; Aubourg, Patrick; Forss-Petter, Sonja

    2010-07-01

    Mutations in the ABCD1 gene cause the clinical spectrum of the neurometabolic disorder X-linked adrenoleukodystrophy/adrenomyeloneuropathy (X-ALD/AMN). Currently, the most efficient therapeutic opportunity for patients with the cerebral form of X-ALD is hematopoietic stem cell transplantation and possibly gene therapy of autologous hematopoietic stem cells. Both treatments, however, are only accessible to a subset of X-ALD patients, mainly because of the lack of markers that can predict the onset of cerebral demyelination. Moreover, for female or male X-ALD patients with AMN, currently only unsatisfying therapeutic opportunities are available. Thus, this review focuses on current and urgently needed future pharmacological therapies. The treatment of adrenal and gonadal insufficiency is well established, whereas applications of immunomodulatory and immunosuppressive drugs have failed to prevent progression of cerebral neuroinflammation. The use of Lorenzo's oil and the inefficacy of lovastatin to normalize very-long-chain fatty acids in clinical trials as well as currently experimental and therefore possible future therapeutic strategies are reviewed. The latter include pharmacological gene therapy mediated by targeted upregulation of ABCD2, the closest homolog of ABCD1, antioxidative drug treatment, small molecule histone deacetylase inhibitors such as butyrates and valproic acid, and other neuroprotective attempts.

  17. Adenoassociated Virus Serotype 9-Mediated Gene Therapy for X-Linked Adrenoleukodystrophy

    PubMed Central

    Gong, Yi; Mu, Dakai; Prabhakar, Shilpa; Moser, Ann; Musolino, Patricia; Ren, JiaQian; Breakefield, Xandra O; Maguire, Casey A; Eichler, Florian S

    2015-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene that encodes a peroxisomal ATP-binding cassette transporter (ABCD1) responsible for transport of CoA-activated very long-chain fatty acids (VLCFA) into the peroxisome for degradation. We used recombinant adenoassociated virus serotype 9 (rAAV9) vector for delivery of the human ABCD1 gene (ABCD1) to mouse central nervous system (CNS). In vitro, efficient delivery of ABCD1 gene was achieved in primary mixed brain glial cells from Abcd1−/− mice as well as X-ALD patient fibroblasts. Importantly, human ABCD1 localized to the peroxisome, and AAV-ABCD1 transduction showed a dose-dependent effect in reducing VLCFA. In vivo, AAV9-ABCD1 was delivered to Abcd1−/− mouse CNS by either stereotactic intracerebroventricular (ICV) or intravenous (IV) injections. Astrocytes, microglia and neurons were the major target cell types following ICV injection, while IV injection also delivered to microvascular endothelial cells and oligodendrocytes. IV injection also yielded high transduction of the adrenal gland. Importantly, IV injection of AAV9-ABCD1 reduced VLCFA in mouse brain and spinal cord. We conclude that AAV9-mediated ABCD1 gene transfer is able to reach target cells in the nervous system and adrenal gland as well as reduce VLCFA in culture and a mouse model of X-ALD. PMID:25592337

  18. Current and Future Pharmacological Treatment Strategies in X-Linked Adrenoleukodystrophy

    PubMed Central

    Berger, Johannes; Pujol, Aurora; Aubourg, Patrick; Forss-Petter, Sonja

    2010-01-01

    Mutations in the ABCD1 gene cause the clinical spectrum of the neurometabolic disorder X-linked adrenoleukodystrophy/adrenomyeloneuropathy (X-ALD/AMN). Currently, the most efficient therapeutic opportunity for patients with the cerebral form of X-ALD is hematopoietic stem cell transplantation and possibly gene therapy of autologous hematopoietic stem cells. Both treatments, however, are only accessible to a subset of X-ALD patients, mainly because of the lack of markers that can predict the onset of cerebral demyelination. Moreover, for female or male X-ALD patients with AMN, currently only unsatisfying therapeutic opportunities are available. Thus, this review focuses on current and urgently needed future pharmacological therapies. The treatment of adrenal and gonadal insufficiency is well established, whereas applications of immunomodulatory and immunosuppressive drugs have failed to prevent progression of cerebral neuroinflammation. The use of Lorenzo's oil and the inefficacy of lovastatin to normalize very-long-chain fatty acids in clinical trials as well as currently experimental and therefore possible future therapeutic strategies are reviewed. The latter include pharmacological gene therapy mediated by targeted upregulation of ABCD2, the closest homolog of ABCD1, antioxidative drug treatment, small molecule histone deacetylase inhibitors such as butyrates and valproic acid, and other neuroprotective attempts. PMID:20626746

  19. Clinical aspects and adrenal functions in eleven Japanese children with X-linked adrenoleukodystrophy.

    PubMed

    Miyoshi, Yoko; Sakai, Norio; Hamada, Yusuke; Tachibana, Makiko; Hasegawa, Yasuhiro; Kiyohara, Yuki; Yamada, Hiroyuki; Murakami, Mari; Kondou, Hiroki; Kimura-Ohba, Shihoko; Mine, Junji; Sato, Tatsuharu; Kamio, Noriko; Ueda, Hitoshi; Suzuki, Yasuhiro; Shiomi, Masashi; Ohta, Hideaki; Shimozawa, Nobuyuki; Ozono, Keiichi

    2010-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a genetic disease associated with demyelination of the central nervous system, adrenocortical insufficiency and accumulation of very long chain fatty acids. It is a clinically heterogeneous disorder ranging from a severe childhood cerebral form to an asymptomatic form. The incidence in Japan is estimated to be between 1:30,000 and 1:50,000 boys as determined by a nationwide retrospective survey between 1990 and 1999, which found no cases with Addison's form. We reviewed the medical records of eleven Japanese boys with X-ALD from 1990 to 2010 in our institute. Eight patients were detected by neuropsychological abnormalities, whereas a higher prevalence of unrecognized adrenocortical insufficiency (5/11: 45%) was observed than previously recognized. While no neurological abnormalities were demonstrated in two brothers, the elder brother had moderate Addison's disease at diagnosis and the presymptomatic younger brother progressed to Addison's disease six months after the diagnosis of X-ALD. Early detection of impaired adrenal function as well as early identification of neurologically presymptomatic patients by genetic analysis is essential for better prognosis. Addison's form might be overlooked in Japan; therefore, X-ALD should be suspected in patients with adrenocortical insufficiency.

  20. X-Linked Recessive form of Nephrogenic Diabetes Insipidus in a 7-Year-Old Boy.

    PubMed

    Janchevska, A; Tasic, V; Gucev, Z; Krstevska-Konstantinova, M; Cheong, H I

    2014-12-01

    Nephrogenic diabetes insipidus (NDI) is caused by the inability of renal collecting duct cells to respond to arginine vasopressin (AVP)/antidiuretic hormone (ADH). We present the case of a 7-year-old boy with a history of excretion of large amounts of dilute urine and polydipsia since infancy. The boy had several vomiting episodes with mild dehydration during the first 3 years of life. There was no evidence of headaches, dizziness or visual problems. He drinks between 2 and 3 L/day and has 24-hour diuresis of 2 liters, now. He has prepubertal appearance with appropriate weight [+0.85 standard deviation score (SDS)] and height (+0.15 SDS) for his age. His intelligence was also normal. The water deprivation test showed low urine osmolality after 8 hours of dehydration. After desmopressin administration, urine osmolality remained low. Serum osmolality was in the normal range for sex and age before and after desmopressin administration. This indicated a nephrogenic form of diabetes insipidus. Molecular analyses revealed a P286L [p.Pro(CCC)286Leu(CTC)] mutation in the AVPR2 gene, that was inherited from his mother. This patient is the first case with genetically confirmed X-linked inherited form of NDI in the Republic of Macedonia. Molecular analysis confirmed the clinical diagnosis and enabled genetic advice for this family.

  1. High-throughput sequencing reveals an altered T cell repertoire in X-linked agammaglobulinemia.

    PubMed

    Ramesh, Manish; Simchoni, Noa; Hamm, David; Cunningham-Rundles, Charlotte

    2015-12-01

    To examine the T cell receptor structure in the absence of B cells, the TCR β CDR3 was sequenced from DNA of 15 X-linked agammaglobulinemia (XLA) subjects and 18 male controls, using the Illumina HiSeq platform and the ImmunoSEQ analyzer. V gene usage and the V-J combinations, derived from both productive and non-productive sequences, were significantly different between XLA samples and controls. Although the CDR3 length was similar for XLA and control samples, the CDR3 region of the XLA T cell receptor contained significantly fewer deletions and insertions in V, D, and J gene segments, differences intrinsic to the V(D)J recombination process and not due to peripheral T cell selection. XLA CDR3s demonstrated fewer charged amino acid residues, more sharing of CDR3 sequences, and almost completely lacked a population of highly modified Vβ gene segments found in control DNA, suggesting both a skewed and contracted T cell repertoire in XLA.

  2. Intronic gene conversion in the evolution of human X-linked color vision genes.

    PubMed

    Shyue, S K; Li, L; Chang, B H; Li, W H

    1994-05-01

    Human red and green visual pigment genes are X-linked duplicate genes. To study their evolutionary history, introns 2 and 4 (1,987 and 1,552 bp, respectively) of human red and green pigment genes were sequenced. Surprisingly, we found that intron 4 sequences of these two genes are identical and that the intron 2 sequences differ by only 0.3%. The low divergences are unexpected because the duplication event producing the two genes is believed to have occurred before the separation of the human and Old World monkey (OWM) lineages. Indeed, the divergences in the two introns are significantly lower than both the synonymous divergence (3.2% +/- 1.1%) and the nonsynonymous divergence (2.0% +/- 0.5%) in the coding sequences (exons 1-6). A comparison of partial sequences of exons 4 and 5 of human and OWM red and green pigment genes supports the hypothesis that the gene duplication occurred before the human-OWM split. In conclusion, the high similarities in the two intron sequences might be due to very recent gene conversion, probably during evolution of the human lineage.

  3. Females with a disorder phenotypically identical to X-linked agammaglobulinemia

    SciTech Connect

    Conley, M.E. ); Sweinberg, S.K. )

    1992-03-01

    Clinical and laboratory findings in two girls with a disorder phenotypically indistinguishable from typical X-linked agammaglobulinemia (XLA) are described. To examine the possibility that subtle defects in the X chromosome might explain the findings, detailed genetic studies were performed on one of these patients. Cytogenetic studies showed a normal 46XX karyotype. Southern blot analysis of her DNA showed that she had inherited a maternal and a paternal allele at sites flanking the locus for typical XLA at Xq22, making a microdeletion or uniparental disomy unlikely. To determine whether both of her X chromosomes could function as the active X, somatic-cell hybrids that selectively retained the active X were produced from her activated T cells. A normal random pattern of X inactivation was seen. Of 21 T-cell hybrids, 3 retained both X chromosomes, 7 had one X as the active X, and 11 had the other X as the active X. The authors have interpreted these studies as indicating that there is an autosomal recessive disorder that is phenotypically identical to XLA.

  4. Non-coding VMA21 deletions cause X-linked myopathy with excessive autophagy.

    PubMed

    Ruggieri, A; Ramachandran, N; Wang, P; Haan, E; Kneebone, C; Manavis, J; Morandi, L; Moroni, I; Blumbergs, P; Mora, M; Minassian, B A

    2015-03-01

    X-linked Myopathy with Excessive Autophagy (XMEA) affects proximal muscles of the lower extremities and follows a progressive course reminiscent of muscular dystrophy. It is caused by mutations in VMA21 whose protein product assembles lysosomes' proton pumps. All XMEA mutations to date have been single-nucleotide substitutions that reduce VMA21 expression, which leads to modest lysosomal pH increase, the first step in the disease's pathogenesis. We now report a new class of XMEA mutations. We identified two VMA21 non-coding microdeletions, one intronic (c.54-16_54-8del), the other in the 3'UTR (c.*13_*104del). Both resulted in a relatively more severe (early ambulation loss), diffuse (extra-ocular and upper extremity involvement), and early (neonatal) onset disease compared to previously reported patients. Our cases highlight the importance of including non-coding regions of VMA21 in genetic testing panels of dystrophies and myopathies. Specific diagnosis of XMEA will be particularly important as therapies aimed at correcting the modest rise in lysosomal pH at the root of this disease are developed.

  5. X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation.

    PubMed

    Sankaran, Vijay G; Ulirsch, Jacob C; Tchaikovskii, Vassili; Ludwig, Leif S; Wakabayashi, Aoi; Kadirvel, Senkottuvelan; Lindsley, R Coleman; Bejar, Rafael; Shi, Jiahai; Lovitch, Scott B; Bishop, David F; Steensma, David P

    2015-04-01

    Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic anemias, and myelodysplastic syndromes. Here, we characterized a family with multiple female individuals who have macrocytic anemia. The proband was noted to have dyserythropoiesis and iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause of the disease, whole-exome sequencing of multiple family members revealed the presence of a mutation in the X chromosomal gene ALAS2, which encodes 5'-aminolevulinate synthase 2, in the affected females. We determined that this mutation (Y365C) impairs binding of the essential cofactor pyridoxal 5'-phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function. X inactivation was not highly skewed in wbc from the affected individuals. In contrast, and consistent with the severity of the ALAS2 mutation, there was a complete skewing toward expression of the WT allele in mRNA from reticulocytes that could be recapitulated in primary erythroid cultures. Together, the results of the X inactivation and mRNA studies illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis through cell-nonautonomous effects. Moreover, our findings highlight the value of whole-exome sequencing in diagnostically challenging cases for the identification of disease etiology and extension of the known phenotypic spectrum of disease. PMID:25705881

  6. A sex-ratio Meiotic Drive System in Drosophila simulans. II: An X-linked Distorter

    PubMed Central

    Tao, Yun; Araripe, Luciana; Kingan, Sarah B; Ke, Yeyan; Xiao, Hailian; Hartl, Daniel L

    2007-01-01

    The evolution of heteromorphic sex chromosomes creates a genetic condition favoring the invasion of sex-ratio meiotic drive elements, resulting in the biased transmission of one sex chromosome over the other, in violation of Mendel's first law. The molecular mechanisms of sex-ratio meiotic drive may therefore help us to understand the evolutionary forces shaping the meiotic behavior of the sex chromosomes. Here we characterize a sex-ratio distorter on the X chromosome (Dox) in Drosophila simulans by genetic and molecular means. Intriguingly, Dox has very limited coding capacity. It evolved from another X-linked gene, which also evolved de nova. Through retrotransposition, Dox also gave rise to an autosomal suppressor, not much yang (Nmy). An RNA interference mechanism seems to be involved in the suppression of the Dox distorter by the Nmy suppressor. Double mutant males of the genotype dox; nmy are normal for both sex-ratio and spermatogenesis. We postulate that recurrent bouts of sex-ratio meiotic drive and its subsequent suppression might underlie several common features observed in the heterogametic sex, including meiotic sex chromosome inactivation and achiasmy. PMID:17988173

  7. X-linked deafness: De novo deletion of a cosmid using dosage studies

    SciTech Connect

    Bitner-Glindzicz, M.; Pembrey, M.E.; deKok, Y.

    1994-09-01

    We have used three polymorphic microsatellite repeats at Xq21, (DXS986, DXS995 and DXS1002) to test for linkage in families with X-linked deafness. Close linkage was demonstrated between all three markers and the disease locus in families with and without a bony abnormality on the CT scan. DXS995 gave a maximum two point lod score of l0.37 with no recombinations. This marker was used to type an additional small sibship. Analysis showed that the two brothers, one deaf and one hearing, both inherited the same maternal allele indicating either the first recombination seen to date or a de novo mutation in the proband. Using a cosmid from the critical region, a deletion was detected in the proband of this sibship. By using a phoshorimager, dosage of an EcoR1 fragment from this cosmid and a control probe was compared to normal subjects and obligate carriers from another family with a similar deletion. Results show that the mother of this isolated case does not carry the deletion, confirming that it is de novo. These markers may be useful for carrier ascertainment in families with a radiological change on CT scan or a pedigree which is linked to Xq21.

  8. A Novel PHEX Mutation in Japanese Patients with X-Linked Hypophosphatemic Rickets

    PubMed Central

    Kawahara, Tetsuya; Watanabe, Hiromi; Omae, Risa; Yamamoto, Toshiyuki; Inazu, Tetsuya

    2015-01-01

    X-linked hypophosphatemic rickets (XLH) is a dominant inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. Inactivating mutations in the gene encoding phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) have been found to be associated with XLH. Here, we report a 16-year-old female patient affected by hypophosphatemic rickets. We evaluated her serum fibroblast growth factor 23 (FGF23) levels and conducted sequence analysis of the disease-associated genes of FGF23-related hypophosphatemic rickets: PHEX, FGF23, dentin matrix protein 1, and ectonucleotide pyrophosphatase/phosphodiesterase 1. She was diagnosed with XLH based on her clinical features and family history. Additionally, we observed elevated FGF23 levels and a novel PHEX exon 9 mutation (c.947G>T; p.Gly316Val) inherited from her father. Although bioinformatics showed that the mutation was neutral, Gly316 is perfectly conserved among humans, mice, and rats, and there were no mutations in other FGF23-related rickets genes, suggesting that in silico analysis is limited in determining mutation pathogenicity. In summary, we present a female patient and her father with XLH harboring a novel PHEX mutation that appears to be causative of disease. Measurement of FGF23 for hypophosphatemic patients is therefore useful for the diagnosis of FGF23-dependent hypophosphatemia. PMID:25861491

  9. Autosomal insertional translocation mimicking an X-linked mode of inheritance.

    PubMed

    Thierry, Gaelle; Pichon, Olivier; Briand, Annaig; Poulain, Damien; Sznajer, Yves; David, Albert; Le Caignec, Cédric

    2013-01-01

    Unbalanced insertional translocations are a rare cause of intellectual disability. An unbalanced insertional translocation is a rare chromosomal imbalance, which may result from a balanced insertional translocation present in a phenotypically normal parent. We report here three brothers with intellectual disability, short stature, microcephaly, craniofacial anomalies and small testes. Since their parents and their sister were all phenotypically normal, the pattern of the family suggested an X-linked mode of inheritance. Surprisingly, we identified by array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) in the three brothers an 8q22.3q23.2 deletion resulting from a balanced insertional translocation present in their healthy father. The deletion encompassed the ZFPM2 gene known to be involved in gonadal development, which is consistent with the small testes and abnormal endocrine dosages in the affected brothers. The present report also illustrates that parental analyses by aCGH or qPCR methods are not sufficient when a de novo deletion or duplication is identified in an affected child and that FISH analysis should be performed on metaphase spreads in both parents to deliver an accurate genetic counseling.

  10. Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance.

    PubMed

    Duszyc, Kinga; Terczynska, Iwona; Hoffman-Zacharska, Dorota

    2015-02-01

    Epilepsy in females with mental retardation (EFMR) is a rare early infantile epileptic encephalopathy (EIEE), phenotypically resembling Dravet syndrome (DS). It is characterised by a variable degree of intellectual deficits and epilepsy. EFMR is caused by heterozygous mutations in the PCDH19 gene (locus Xq22.1) encoding protocadherin-19, a protein that is highly expressed during brain development. The protein is involved in cell adhesion and probably plays an important role in neuronal migration and formation of synaptic connections. EFMR is considered X-linked of variable mutations' penetrance. Mutations in the PCDH19 gene mainly arise de novo, but if inherited, they show a unique pattern of transmission. Females with heterozygous mutations are affected, while hemizygous males are not, regardless of mutation carriage. This singular mode might be explained by cell interference as a pathogenic molecular mechanism leading to neuronal dysfunction. Recently, PCDH19-related EIEE turned out to be more frequent than initially thought, contributing to around 16% of cases (25% in female groups) in the SCN1A-negative DS-like patients. Therefore, the PCDH19 gene is now estimated to be the second, after SCN1A, most clinically relevant gene in epilepsy.

  11. Mutations in PHKA2 are responsible for X-linked liver glycogen storage disease

    SciTech Connect

    Hendrickx, J.; Coucke, P.; Dams, E.

    1994-09-01

    X-linked liver glycogenosis type I (XLG I) is due to a deficiency of phosphorylase kinase (PHK), a key enzyme in the control of glycogen breakdown. XLG I is the most common glycogen storage disease. Patients show hepatomegaly, growth retardation and elevation of liver enzymes as their main clinical symptoms. We assigned the XLG I gene to the chromosomal region Xp22 by linkage analysis in six XLG I families. As the liver {alpha}-subunit of PHK (PHKA2) was also localized to Xp22, PHKA2 was considered a candidate gene for XLG I. In this study, we searched for mutations in 6 exons of the PHDA2 gene of 9 unrelated XLG I patients by SSCP analysis. This revealed three point mutations present in three different patients. Two of these mutations introduce a premature stop codon leading to a truncated protein. The third mutation abolishes a 5{prime} splice site consensus sequence leading to exon skipping. All three mutations therefore result in a PHKA2 protein that lacks several amino acids, what most probably affects enzyme function or stability. These findings indicate that PHKA2 is the XLG I gene.

  12. Postural leg tremor in X-linked spinal and bulbar muscular atrophy.

    PubMed

    Nishiyama, Ayumi; Sugeno, Naoto; Tateyama, Maki; Nishiyama, Shuhei; Kato, Masaaki; Aoki, Masashi

    2014-05-01

    X-linked spinal and bulbar muscular atrophy (SBMA) is an adult-onset neuromuscular disorder caused by a CAG repeat expansion in the androgen receptor gene. Postural hand tremor is well known as a non-motor neuron sign, but to our knowledge postural leg tremor has not been reported. We studied the occurrence and physiological features of postural leg tremor in 12 male patients (38-64 years old) with genetically proven SBMA. Three patients had postural leg tremor with a frequency of 4-7Hz. In these patients, sensory nerve action potential (SNAP) was not detected in the lower limbs. There were significant differences between the patients with postural leg tremor and those without postural leg tremor in both the SNAP of the sural nerve and the length of the CAG repeat. Phenotypical differences between shorter CAG repeats, which indicate a sensory-dominant phenotype, and longer CAG repeats, which indicate a motor-dominant phenotype, have been previously reported. In the present study, 60% of patients with shorter CAG repeats (<47) showed leg tremor and none of the patients with longer CAG repeats (≥47) did. Postural leg tremor could be a clinical feature that predicts shorter CAG repeats of the androgen receptor gene.

  13. Short Stature in Partially Corrected X-Linked Severe Combined Immunodeficiency- Suboptimal Response to Growth Hormone

    PubMed Central

    De Ravin, Suk See; Shum, Elaine; Zarember, Kol A.; Rezvani, Geoffrey; Rosenfeld, Ron G.; Stratakis, Constantine A.; Malech, Harry L.

    2009-01-01

    Background X-linked severe combined immunodeficiency (XSCID) results from defects in the common cytokine receptor γ chain (γc) required for signaling by receptors for interleukin (IL)-2, -4, -7, -9, -15, and -21 (1). Following haploidentical bone marrow transplant without myelo-conditioning for XSCID, most patients achieve partial reconstitution(2) often limited to T lymphocytes. Many partially corrected patients manifest extreme short stature (<5th percentile). Previous reports have implicated γc in growth hormone (GH) receptor signaling, thus severe growth failure in XSCID may be related to the underlying γc defect. Objective To evaluate the GH/insulin-like growth factor (IGF-1) axes in 3 children with XSCID and partial immune reconstitution with profound growth failure. Methods The IGF-1 generation test was performed by administering recombinant GH subcutaneously for 5 days, and measuring serum levels for IGF-1 before GH injection, and on days 5 and 8. Results Study of the somatotropic axis revealed profoundly diminished IGF-1 production following rGH challenge in all 3 patients. Conclusion The data indicate that the GH/IGF-1 axes in these partially corrected XSCID patients with severe short stature is profoundly impaired, and supports previous studies suggesting that the underlying γc defect may contribute to the severe growth failure in XSCID. This supports a role for defective γc in extreme short stature of XSCID, and raises the possibility of recombinant IGF-1 treatment to bypass this defect. PMID:19189700

  14. Regulation of X-linked gene expression during early mouse development by Rlim

    PubMed Central

    Wang, Feng; Shin, JongDae; Shea, Jeremy M; Yu, Jun; Bošković, Ana; Byron, Meg; Zhu, Xiaochun; Shalek, Alex K; Regev, Aviv; Lawrence, Jeanne B; Torres, Eduardo M; Zhu, Lihua J; Rando, Oliver J; Bach, Ingolf

    2016-01-01

    Mammalian X-linked gene expression is highly regulated as female cells contain two and male one X chromosome (X). To adjust the X gene dosage between genders, female mouse preimplantation embryos undergo an imprinted form of X chromosome inactivation (iXCI) that requires both Rlim (also known as Rnf12) and the long non-coding RNA Xist. Moreover, it is thought that gene expression from the single active X is upregulated to correct for bi-allelic autosomal (A) gene expression. We have combined mouse genetics with RNA-seq on single mouse embryos to investigate functions of Rlim on the temporal regulation of iXCI and Xist. Our results reveal crucial roles of Rlim for the maintenance of high Xist RNA levels, Xist clouds and X-silencing in female embryos at blastocyst stages, while initial Xist expression appears Rlim-independent. We find further that X/A upregulation is initiated in early male and female preimplantation embryos. DOI: http://dx.doi.org/10.7554/eLife.19127.001 PMID:27642011

  15. Genetic mapping of X-linked ocular albinism: Linkage analysis in a large Newfoundland kindred

    SciTech Connect

    Charles, S.J.; Moore, A.T.; Barton, D.E.; Yates, J.R.W. ); Green, J.S. )

    1993-04-01

    Genetic linkage studies in a large Newfoundland family affected by X-linked ocular albinism (OA1) showed linkage to markers from Xp22.3. One recombinant mapped the disease proximal to DXS143 (dic56) and two recombinants mapped the disease distal to DXS85 (782). Combining the data with that from 16 British families previously published confirmed close linkage between OA1 and DXS143 (dic56; Z[sub max] = 21.96 at [theta] = 0.01, confidence interval (CI) 0.0005--0.05) and linkage to DXS85 (782; Z[sub max] = 17.60 at [theta] = 0.07, CI = 0.03--0.13) and DXS237 (GMGX9; Z[sub max] = 15.20 at [theta] = 0.08, CI = 0.03--0.15). Multipoint analysis (LINKMAP) gave the most likely order as Xpter-XG-DXS237-DXS143-OA1-DXS85, with odds of 48:1 over the order Xpter-XG-DXS237-OA1-DXS143-DXS85, and odds exceeding 10[sup 10]:1 over other locations for the disease locus. 11 refs., 1 fig., 1 tab.

  16. How do Mutations in GJB1 Cause X-linked Charcot-Marie-Tooth Disease?

    PubMed Central

    Kleopa, Kleopas A.; Abrams, Charles K.; Scherer, Steven S.

    2012-01-01

    The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive weakness, atrophy, and sensory abnormalities that are most pronounced in the distal extremities. Some patients have CNS manifestations. Affected males have moderate to severe symptoms, whereas heterozygous females are usually less affected. Neurophysiology shows intermediate slowing of conduction and length-dependent axonal loss. Nerve biopsies show more prominent axonal degeneration than de/remyelination. Mutations in GJB1, the gene that encodes the gap junction (GJ) protein connexin32 (Cx32) cause CMT1X; more than 400 different mutations have been described. Many Cx32 mutants fail to form functional GJs, or form GJs with abnormal biophysical properties. Schwann cells and oligodendrocytes express Cx32, and the GJs formed by Cx32 play an important role in the homeostasis of myelinated axons. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. Effective therapies remain to be developed. PMID:22771394

  17. Sushi repeat protein X-linked 2, a novel mediator of angiogenesis.

    PubMed

    Miljkovic-Licina, Marijana; Hammel, Philippe; Garrido-Urbani, Sarah; Bradfield, Paul F; Szepetowski, Pierre; Imhof, Beat A

    2009-12-01

    On appropriate stimuli, quiescent endothelial cells start to proliferate and form de novo blood vessels through angiogenesis. To further define molecular mechanisms accompanying the activation of endothelial cells during angiogenesis, we identified genes that were differentially regulated during this process using microarray analyses. In this work, we established a regulatory role for Sushi repeat protein X-linked 2 (Srpx2) in endothelial cell remodeling during angiogenesis. In particular, silencing of Srpx2 using small interfering RNAs (siRNAs) specifically attenuated endothelial cell migration and delayed angiogenic sprout formation. In vivo, Srpx2 expression was detected in de novo formation of blood vessels in angiogenic tissues by in situ mRNA hybridization and immunostaining. Pulldown experiments identified Srpx2 as a ligand for vascular uPAR, a key molecule involved in invasive migration of angiogenic endothelium. Immunostaining revealed coexpression of the Srpx2 and uPAR on vascular endothelium. These findings suggest that Srpx2 regulates endothelial cell migration and tube formation and provides a new target for modulating angiogenesis.

  18. Clinical diversity and chromosomal localization of X-linked cone dystrophy (COD1).

    PubMed Central

    Hong, H. K.; Ferrell, R. E.; Gorin, M. B.

    1994-01-01

    X-linked progressive cone dystrophy (COD1) causes progressive deterioration of visual acuity, deepening of central scotomas, macular changes, and bull's-eye lesions. The cone electroretinography (ERG) is variably abnormal in affected males, and the rod ERG may also be abnormal. The clinical picture of heterozygous females ranges from asymptomatic to a widespread spectrum of cone-mediated dysfunction. A prior linkage study demonstrated linkage between the COD1 locus and the marker locus DXS84, assigned to Xp21.1, with no recombination. In the present study, we have clinically characterized a large four-generation family with COD1 and have performed a linkage analysis using seven polymorphic markers on the short arm of the X chromosome. No recombination was observed between the disease and the marker loci DXS7 and MAOA, suggesting that the location of COD1 is in the region Xp11.3, distal to DXS84 and proximal to ARAF1. Images Figure 2 PMID:7977377

  19. Expression of X-linked Inhibitor of Apoptosis Protein in Neoplastic Thyroid Disorder

    PubMed Central

    Yim, Ji Hye; Kim, Sun A; Kim, Won Gu; Jeon, Min Ji; Han, Ji Min; Sung, Tae Yon; Kim, Tae Yong; Kim, Won Bae; Hong, Suck Joon; Shong, Young Kee; Gong, Gyungyub

    2011-01-01

    X-linked inhibitor of apoptosis protein (XIAP) is associated with tumor genesis, growth, progression and metastasis, and acts by blocking caspase-mediated apoptosis. In the present study, we sought to evaluate the expression patterns of XIAP in various neoplastic thyroid disorders and determine the association between XIAP expression and clinicopathologic factors. Expression of XIAP was evaluated with immunohistochemical staining using monoclonal anti-XIAP in 164 specimens of conventional papillary thyroid carcinoma (PTC) and 53 specimens of other malignant or benign thyroid tumors. XIAP positivity was observed in 128 (78%) of the 164 conventional PTC specimens. Positive rates of XIAP expression in follicular variant PTC, follicular, medullary, poorly differentiated, and anaplastic thyroid carcinoma specimens were 20%, 25%, 38%, 67%, and 38%, respectively. Six nodular hyperplasia specimens were negative and 1 of 7 follicular adenomas (8%) was positive for XIAP. Lateral neck lymph node metastases were more frequent in patients negative for XIAP expression (P = 0.01). Immunohistochemical staining for XIAP as a novel molecular marker may thus be helpful in the differential diagnosis of thyroid cancer. Moreover, high XIAP expression in conventional PTC is strongly associated with reduced risk of lateral neck lymph node metastasis. PMID:21935275

  20. Deficiency of X-Linked Protein Kinase Nrk during Pregnancy Triggers Breast Tumor in Mice.

    PubMed

    Yanagawa, Takayo; Denda, Kimitoshi; Inatani, Takuya; Fukushima, Toshiaki; Tanaka, Toshiaki; Kumaki, Nobue; Inagaki, Yutaka; Komada, Masayuki

    2016-10-01

    The onset and/or growth of breast tumor are controlled, at least in part, by estrogen. Therefore, to prevent the development of breast tumor, estrogen-dependent proliferation of mammary epithelial cells during pregnancy needs to be suppressed once the mammary gland is fully developed to enable lactation. However, the underlying molecular mechanisms remain unknown. Nrk is an X-linked protein serine/threonine kinase in the germinal center kinase family. Herein, we demonstrate a frequent occurrence of breast tumors in homozygous and heterozygous Nrk mutant mice that have experienced pregnancy/parturition. The tumors never developed in the mutant mice without a history of pregnancy/parturition. They exhibited histopathological features of noninvasive tubular adenocarcinoma, and expressed estrogen receptor α. At late gestation when estrogen receptor α expression was significantly reduced in the wild-type mammary gland, grossly normal mammary glands in the pregnant Nrk mutant mice occasionally contained hyperplastic foci continuously expressing the receptor. Consistently, Nrk expression was induced in the wild-type mammary gland at this period of pregnancy. On the other hand, the pregnant Nrk mutant mice also showed elevated blood estrogen levels at late gestation. We suggest that Nrk suppresses the excessive proliferation of mammary epithelial cells during pregnancy, and the impairment of this regulatory system leads to frequent occurrence of breast tumor in Nrk mutant mice. PMID:27634343

  1. [X-linked hyper-IGM syndrome associated to sclerosing cholangitis and gallbladder neoplasm: clinical case].

    PubMed

    Rodríguez, Cristián; Carrión, Flavio; Marinovic, María Angélica; Chávez, Eduardo; Preisler, Jessica; Pooley, Francisco; Futatani, Takeshi; Ochs, Hans D

    2003-03-01

    We report a 11 years old male diagnosed as a X-linked hyper-IgM syndrome that presented with recurrent infections and sclerosing cholangitis and later developed a gallbladder cancer. Immunological evaluation showed decreased levels of serum IgG and IgA with elevated levels of IgM. Study of CD40 ligand expression on mitogen activated peripheral blood mononuclear cells revealed total absence of this marker on T lymphocytes. Molecular analysis detected, in the patient and his mother, a nonsense mutation in exon 1 of the transmembrane segment of the CD40 ligand. He also presented elevation of alkaline phosphatases and mild elevation of liver enzymes. Liver biopsy demonstrated the presence of idiopathic sclerosing cholangitis. The patient was started on monthly IVIG therapy at 400 mg/kg, as well as ursodeoxycholic acid and vitamin E, with normalization of his IgG and IgM levels a decrease in the incidence of infections and normalization of liver function. Three years after diagnosis, we detected the presence of polyps inside the gallbladder that were reported at biopsy as adenocarcinoma. He underwent hepatic bisegmentectomy (VI B-V) and local lymphadenectomy.

  2. A mouse model of X-linked intellectual disability associated with impaired removal of histone methylation

    PubMed Central

    Iwase, Shigeki; Brookes, Emily; Agarwal, Saurabh; Badeaux, Aimee I; Ito, Hikaru; Vallianatos, Christina N; Tomassy, Giulio Srubek; Kasza, Tomas; Lin, Grace; Thompson, Andrew; Gu, Lei; Kwan, Kenneth Y.; Chen, Chinfei; Sartor, Maureen A.; Egan, Brian; Xu, Jun; Shi, Yang

    2015-01-01

    Mutations in a number of chromatin modifiers are associated with human neurological disorders. KDM5C, a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase, is frequently mutated in X-linked intellectual disability (XLID) patients. Here, we report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior and memory, and aggression. Kdm5c-knockout brains exhibit impaired dendritic arborization, spine abnormalities, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels. Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries. In summary, our mouse behavioral data strongly suggests that KDM5C mutations are causal to XLID. Furthermore, our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes. PMID:26804915

  3. GPR143 mutational analysis in two Italian families with X-linked ocular albinism.

    PubMed

    Micale, Lucia; Augello, Bartolomeo; Fusco, Carmela; Turturo, Maria Giuseppina; Granatiero, Matteo; Piemontese, Maria Rosaria; Zelante, Leopoldo; Cecconi, Antonella; Merla, Giuseppe

    2009-08-01

    X-linked ocular albinism type 1 (OA1) is caused by mutations in G protein-coupled receptor 143 (GPR143) gene, which encodes a membrane glycoprotein localized to melanosomes. GPR143 mainly affects pigment production in the eye, resulting in optic changes associated with albinism, including hypopigmentation of the retina, nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic fibers, and reduced visual acuity. We report the mutational analysis of the GPR143 gene on two unrelated families with OA1 using direct sequencing and real-time quantitative polymerase chain reaction. We identified the c.564_565delCT, a 2-bp deletion in family 1, and we mapped the breakpoints at nucleotide level of the novel intragenic deletion g.5360_6371del1012, encompassing exon 2, in family 2. Our results confirm that GPR143 is the major locus for OA1 and that exon 2 is a region of high susceptibility to deletions. Finally, we emphasize the quantitative polymerase chain reaction as a valid tool for diagnosis of deletions in the GPR143 gene. PMID:19604113

  4. Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth

    PubMed Central

    Steward, C G; Newbury-Ecob, R A; Hastings, R; Smithson, S F; Tsai-Goodman, B; Quarrell, O W; Kulik, W; Wanders, R; Pennock, M; Williams, M; Cresswell, J L; Gonzalez, I L; Brennan, P

    2010-01-01

    Objective Barth Syndrome (BTHS) is an X-linked multisystem disorder (OMIM 302060) usually diagnosed in infancy and characterized by cardiac problems [dilated cardiomyopathy (DCM) ± endocardial fibroelastosis (EFE) ± left ventricular non-compaction (LVNC)], proximal myopathy, feeding problems, growth retardation, neutropenia, organic aciduria and variable respiratory chain abnormalities. We wished to determine whether BTHS had a significant impact on fetal and perinatal health in a large cohort of family groups originating from a defined region. Method Case note review on 19 families originating from the UK and known to the Barth Syndrome Service of the Bristol Royal Hospital for Children. Results Details are presented on six kindreds (32%) with genetically and biochemically proven BTHS that demonstrate a wider phenotype including male fetal loss, stillbirth and severe neonatal illness or death. In these families, 9 males were stillborn and 14 died as neonates or infants but there were no losses of females. BTHS was definitively proven in five males with fetal onset of DCM ± hydrops/EFE/LVNC. Conclusion These findings stress the importance of considering BTHS in the differential diagnosis of unexplained male hydrops, DCM, EFE, LVNC or pregnancy loss, as well as in neonates with hypoglycemia, lactic acidosis and idiopathic mitochondrial disease. Copyright © 2010 John Wiley & Sons, Ltd. PMID:20812380

  5. X-Linked Recessive form of Nephrogenic Diabetes Insipidus in a 7-Year-Old Boy

    PubMed Central

    Janchevska, A; Tasic; Gucev, Z; Krstevska-Konstantinova, M; Cheong, HI

    2014-01-01

    Nephrogenic diabetes insipidus (NDI) is caused by the inability of renal collecting duct cells to respond to arginine vasopressin (AVP)/antidiuretic hormone (ADH). We present the case of a 7-year-old boy with a history of excretion of large amounts of dilute urine and polydipsia since infancy. The boy had several vomiting episodes with mild dehydration during the first 3 years of life. There was no evidence of headaches, dizziness or visual problems. He drinks between 2 and 3 L/day and has 24-hour diuresis of 2 liters, now. He has prepubertal appearance with appropriate weight [+0.85 standard deviation score (SDS)] and height (+0.15 SDS) for his age. His intelligence was also normal. The water deprivation test showed low urine osmolality after 8 hours of dehydration. After desmopressin administration, urine osmolality remained low. Serum osmolality was in the normal range for sex and age before and after desmopressin administration. This indicated a nephrogenic form of diabetes insipidus. Molecular analyses revealed a P286L [p.Pro(CCC)286Leu(CTC)] mutation in the AVPR2 gene, that was inherited from his mother. This patient is the first case with genetically confirmed X-linked inherited form of NDI in the Republic of Macedonia. Molecular analysis confirmed the clinical diagnosis and enabled genetic advice for this family. PMID:25937802

  6. Characterization of 11 novel mutations in the X-linked chronic granulomatous disease (CYBB gene).

    PubMed

    Gérard, B; El Benna, J; Alcain, F; Gougerot-Pocidalo, M A; Grandchamp, B; Chollet-Martin, S

    2001-08-01

    The most frequent form of chronic granulomatous disease (CGD) is caused by inactivation of the CYBB gene, which encodes the gp91-phox subunit of phagocyte NADPH oxidase. This defect prevents phagocytes from producing reactive oxygen species and thus from eradicating bacterial and fungal infections. We investigated 16 unrelated male patients with suspected X-linked CGD and gp91-phox deficiency. A mutation was found in the CYBB gene of all 16 patients, and 11 of these mutations were novel. Eleven patients (69%) had a point mutation (84G>A in two unrelated patients, and 177C>G, 217C>T, 388C>T, 676C>T, 691C>T, 868C>T, 919A>C, 1384G>T and T1514G in one case each, yielding W28X, C59W, R73X, R130X, R226X, Q231X, R290X, T307P, E462X, L505R gp-91phox). One patient had an in-frame deletion removing two amino acids (R54 and A55). Finally, insertions or duplications were found in four patients (from +1 to +31 bases). Overall, 12 (75%) of the mutations led to the production of a truncated protein. No clear correlation was found between clinical manifestations and genomic/biochemical alterations. Thirteen mothers could be tested, and all were carriers. Hum Mutat 18:163, 2001.

  7. X-linked hypophosphatemic rickets: enamel abnormalities and oral clinical findings.

    PubMed

    Cremonesi, Ilaria; Nucci, Cesare; D'Alessandro, Giovanni; Alkhamis, Nadia; Marchionni, Silvia; Piana, Gabriela

    2014-01-01

    X-linked hypophosphatemia (XLH) is a genetic disorder related to alterations in bones and teeth formation, due to low levels of phosphate in blood. Oral findings in XLH have been enamel and dentine abnormalities, high pulp horns, large pulp chambers, and some cases of periapical abscesses related to teeth without caries or traumatic injuries. The aim of our study was to assess the presence of enamel alterations, such as microclefts and/or structure defects in patients with XLH and give guidelines of prevention of XLH dental complications. History taking, oral clinical and radiological examination in 10 young patients affected by XLH (average age of 9) and in 6 patients without XLH (average age of 8). Impressions were performed on the vestibular surfaces of teeth in order to obtain replicas. The replicas were analyzed using scanning electron microscope (SEM) and compared to replicas of control group. The images of replicas of XLH patients showed deep microclefts and irregular enamel surface structure compared to replicas of control group. The replica of a patient with spontaneous periapical abscesses showed numerous enamel crater-shaped depressions and deep microcleavages penetrating into the enamel thickness. In absence of caries or fractures, the abscesses pathogenesis may be related to microcleavages of the enamel and dentin, which allow bacterial invasion of the pulp. There could be a relationship between XLH disease and enamel abnormalities. PMID:24677288

  8. PROTECTIVE LEVELS OF VARICELLA-ZOSTER ANTIBODY DID NOT EFFECTIVELY PREVENT CHICKENPOX IN AN X-LINKED AGAMMAGLOBULINEMIA PATIENT.

    PubMed

    Nobre, Fernanda Aimée; Gonzalez, Isabela Garrido da Silva; de Moraes-Pinto, Maria Isabel; Costa-Carvalho, Beatriz Tavares

    2015-01-01

    We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG) therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection.

  9. Genetic heterogeneity of syndromic X-linked recessive microphthalmia-anophthalmia: is Lenz microphthalmia a single disorder?

    PubMed

    Ng, David; Hadley, Donald W; Tifft, Cynthia J; Biesecker, Leslie G

    2002-07-15

    Nonsyndromic congenital microphthalmia or anophthalmia is a heterogeneous malformation with autosomal dominant, autosomal recessive, and X-linked modes of inheritance. Lenz microphthalmia syndrome comprises microphthalmia with mental retardation, malformed ears, skeletal anomalies, and is inherited in an X-linked recessive pattern. Prior studies have shown linkage of both isolated (or nonsyndromic) anophthalmos (ANOP1, [MIM 301590]) and Lenz syndrome [MIM 309800] to Xq27-q28. Nonsyndromic colobomatous microphthalmia [MIM 300345] has been linked to Xp11.4-Xq11.1. We describe a five-generation African-American family with microphthalmia or anophthalmia, mental retardation, and urogenital anomalies, in an X-linked recessive inheritance pattern, consistent with Lenz syndrome. Initial linkage analysis with microsatellite markers excluded the region in Xq27-q28 previously reported as a candidate region for ANOP1 [MIM 301590]. An X-chromosome scan revealed linkage to a 10-cM region between markers DXS228 and DXS992 in Xp11.4-p21.2. Multipoint analysis gave a maximum LOD score of 2.46 at marker DXS993. These data show that X-linked recessive syndromic microphthalmia exhibits genetic heterogeneity. In addition, it suggests that Lenz microphthalmia syndrome, previously thought to be a single disorder, may represent an amalgam of two distinct disorders.

  10. PROTECTIVE LEVELS OF VARICELLA-ZOSTER ANTIBODY DID NOT EFFECTIVELY PREVENT CHICKENPOX IN AN X-LINKED AGAMMAGLOBULINEMIA PATIENT.

    PubMed

    Nobre, Fernanda Aimée; Gonzalez, Isabela Garrido da Silva; de Moraes-Pinto, Maria Isabel; Costa-Carvalho, Beatriz Tavares

    2015-01-01

    We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG) therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection. PMID:26603238

  11. An X-linked sex ratio distorter in Drosophila simulans that kills or incapacitates both noncarrier sperm and sons.

    PubMed

    Rice, William R

    2014-10-01

    Genomic conflict occurs when a genomic component gains a reproductive advantage at the expense of the organism as a whole. X-linked segregation distorters kill or incapacitate Y-bearing sperm, thereby gaining a transmission advantage but also reducing male fertility and generating a female-biased sex ratio. When some damaged, Y-bearing sperm survive and fertilize eggs, then the segregation distortion phenotype could be expanded by harming or killing sons in the next generation. X-linked son-killers are predicted by theory to be favored by natural selection and evolve when brothers and sisters compete for shared limiting resources and/or when brothers reduce the inclusive fitness of their sisters via sib-mating-a phenomenon called SA-zygotic drive. Here I develop and use a process-of-elimination screen to show that an unclassified X-linked sex ratio distorter (skew) in Drosophila simulans kills or incapacitates noncarrier sperm and also kills a substantial proportion of sons, i.e., it has both a segregation distortion and a SA-zygotic drive phenotype. There are three unique X-linked segregation distorters known to occur in D. simulans named Winters, Durham, and Paris. Autosomal-dominant suppressors of Winters (Nmy) and Durham (Tmy) failed to suppress skew. A Y-linked suppressor of Paris, however, did suppress skew, and a recombination test failed to detect recombinants between these two sex ratio distorters, indicating that they are tightly linked and plausibly identical or allelic. Son-killing may be an important yet unrecognized component of other X-linked segregation distorters.

  12. An X-Linked Sex Ratio Distorter in Drosophila simulans That Kills or Incapacitates Both Noncarrier Sperm and Sons

    PubMed Central

    Rice, William R.

    2014-01-01

    Genomic conflict occurs when a genomic component gains a reproductive advantage at the expense of the organism as a whole. X-linked segregation distorters kill or incapacitate Y-bearing sperm, thereby gaining a transmission advantage but also reducing male fertility and generating a female-biased sex ratio. When some damaged, Y-bearing sperm survive and fertilize eggs, then the segregation distortion phenotype could be expanded by harming or killing sons in the next generation. X-linked son-killers are predicted by theory to be favored by natural selection and evolve when brothers and sisters compete for shared limiting resources and/or when brothers reduce the inclusive fitness of their sisters via sib-mating—a phenomenon called SA-zygotic drive. Here I develop and use a process-of-elimination screen to show that an unclassified X-linked sex ratio distorter (skew) in Drosophila simulans kills or incapacitates noncarrier sperm and also kills a substantial proportion of sons, i.e., it has both a segregation distortion and a SA-zygotic drive phenotype. There are three unique X-linked segregation distorters known to occur in D. simulans named Winters, Durham, and Paris. Autosomal-dominant suppressors of Winters (Nmy) and Durham (Tmy) failed to suppress skew. A Y-linked suppressor of Paris, however, did suppress skew, and a recombination test failed to detect recombinants between these two sex ratio distorters, indicating that they are tightly linked and plausibly identical or allelic. Son-killing may be an important yet unrecognized component of other X-linked segregation distorters. PMID:25081980

  13. Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A Paradigm of Immunodeficiency with Autoimmunity

    PubMed Central

    Barzaghi, Federica; Passerini, Laura; Bacchetta, Rosa

    2012-01-01

    Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID) due to mutations of FOXP3, a key transcription factor for naturally occurring (n) regulatory T (Treg) cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type-1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia can develop in patients who survive the initial acute phase. The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is hematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease. This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed. PMID:23060872

  14. Further localization of X-linked hydrocephalus in the chromosomal region Xq28

    PubMed Central

    Willems, Patrick J.; Vits, Lieve; Raeymaekers, Peter; Beuten, Joke; Coucke, Paul; Holden, Jeanette J. A.; Van Broeckhoven, Christine; Warren, Stephen T.; Sagi, Michal; Robinson, David; Dennis, Nick; Friedman, Kenneth J.; Magnay, Dorothy; Lyonnet, Stanislas; White, Bradley N.; Wittwer, Bärbel H.; Aylsworth, Arthur S.; Reicke, Sigrid

    1992-01-01

    X-linked hydrocephalus (HSAS) is the most frequent genetic form of hydrocephalus. Clinical symptoms of HSAS include hydrocephalus, mental retardation, clasped thumbs, and spastic paraparesis. Recently we have assigned the HSAS gene to Xq28 by linkage analysis. In the present study we used a panel of 18 Xq27-q28 marker loci to further localize the HSAS gene in 13 HSAS families of different ethnic origins. Among the Xq27-q28 marker loci used, DXS52, DXS15, and F8C gave the highest combined lod scores, of 14.64, 6.53 and 6.33, respectively, at recombination fractions of .04, 0, and .05, respectively. Multipoint linkage analysis localizes the HSAS gene in the telomeric part of the Xq28 region, with a maximal lod score of 20.91 at 0.5 cM distal to DXS52. Several recombinations between the HSAS gene and the Xq28 markers DXS455, DXS304, DXS305, and DXS52 confirm that the HSAS locus is distal to DXS52. One crossover between HSAS and F8C suggests the HSAS gene to be proximal to F8C. Therefore, data from multipoint linkage analysis and the localization of key crossovers indicate that the HSAS gene is most likely located between DXS52 and F8C. This high-resolution genetic mapping places the HSAS locus within a region of <2 Mb in length, which is now amenable to positional cloning. ImagesFigure 2Figure 3 PMID:1642232

  15. Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.

    PubMed

    Daly, Adrian F; Yuan, Bo; Fina, Frederic; Caberg, Jean-Hubert; Trivellin, Giampaolo; Rostomyan, Liliya; de Herder, Wouter W; Naves, Luciana A; Metzger, Daniel; Cuny, Thomas; Rabl, Wolfgang; Shah, Nalini; Jaffrain-Rea, Marie-Lise; Zatelli, Maria Chiara; Faucz, Fabio R; Castermans, Emilie; Nanni-Metellus, Isabelle; Lodish, Maya; Muhammad, Ammar; Palmeira, Leonor; Potorac, Iulia; Mantovani, Giovanna; Neggers, Sebastian J; Klein, Marc; Barlier, Anne; Liu, Pengfei; Ouafik, L'Houcine; Bours, Vincent; Lupski, James R; Stratakis, Constantine A; Beckers, Albert

    2016-04-01

    Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

  16. Extraordinary sequence divergence at Tsga8, an X-linked gene involved in mouse spermiogenesis.

    PubMed

    Good, Jeffrey M; Vanderpool, Dan; Smith, Kimberly L; Nachman, Michael W

    2011-05-01

    The X chromosome plays an important role in both adaptive evolution and speciation. We used a molecular evolutionary screen of X-linked genes potentially involved in reproductive isolation in mice to identify putative targets of recurrent positive selection. We then sequenced five very rapidly evolving genes within and between several closely related species of mice in the genus Mus. All five genes were involved in male reproduction and four of the genes showed evidence of recurrent positive selection. The most remarkable evolutionary patterns were found at Testis-specific gene a8 (Tsga8), a spermatogenesis-specific gene expressed during postmeiotic chromatin condensation and nuclear transformation. Tsga8 was characterized by extremely high levels of insertion-deletion variation of an alanine-rich repetitive motif in natural populations of Mus domesticus and M. musculus, differing in length from the reference mouse genome by up to 89 amino acids (27% of the total protein length). This population-level variation was coupled with striking divergence in protein sequence and length between closely related mouse species. Although no clear orthologs had previously been described for Tsga8 in other mammalian species, we have identified a highly divergent hypothetical gene on the rat X chromosome that shares clear orthology with the 5' and 3' ends of Tsga8. Further inspection of this ortholog verified that it is expressed in rat testis and shares remarkable similarity with mouse Tsga8 across several general features of the protein sequence despite no conservation of nucleotide sequence across over 60% of the rat-coding domain. Overall, Tsga8 appears to be one of the most rapidly evolving genes to have been described in rodents. We discuss the potential evolutionary causes and functional implications of this extraordinary divergence and the possible contribution of Tsga8 and the other four genes we examined to reproductive isolation in mice. PMID:21186189

  17. X-linked nephrogenic diabetes insipidus: From the ship Hopewell to RFLP studies

    SciTech Connect

    Bichet, D.G.; Lonergan, M.; Arthus, M.F.; Ligier, S.; Kluge, R. ); Hendy, G.N.; Pausova, Z.; Zingg, H.; Morgan, K.; Saenger, P. )

    1992-11-01

    Nephrogenic diabetes insipidus (NDI; designated 304800 in Mendelian Inheritance in Man) is an X-linked disorder with abnormal renal and extrarenal V[sub 2] vasopression receptor responses. The mutant gene has been mapped to Xq28 by analysis of RFLPs, and tight linkage between DXS52 and DNI has been reported. In 1969, Bode and Crawford proposed, under the term, the Hopewell hypothesis' that most cases in North America could be traced to descendants of Ulster Scots who arrived in Nova Scotia in 1761 on the ship Hopewell. They also suggested a link between this family and a large Mormon pedigree. DNA samples obtained from 13 independent affected families, including 42 members of the Hopewell and Mormon pedigrees, were analyzed with probes in the Xq28 region. Genealogical reconstructions were performed. Linkage between NDI and DXS304 (probe U6:2.spl), DXS305 (St35-691), DXS52 (St14-1), DXS15 (DX13), and F8C (F814) showed no recombination in 12 families, with a maximum lod score of 13.5 for DXS52. A recombinant between NDI and DXS304, DXS305, was identified in one family. The haplotype segregating with the disease in the Hopewell pedigree was not shared by other North American families. PCR analysis of the St14 VNTR allowed the distinction of two alleles that were not distinguishable by Southern analysis. Carrier status was predicted in 24 of 26 at-risk females. The Hopewell hypothesis cannot explain the origin of NDI in many of the North American families, since they have no apparent relationship with the Hopewell earlier settlers, either by haplotype or by genealogical analysis. PCR analysis of the DXS52 VNTR in NDI families is very useful for carrier testing and presymptomatic diagnosis, which can prevent the first manifestations of dehydration. 39 refs., 7 figs., 3 tabs.

  18. High-resolution mapping of the x-linked hypohidrotic ectodermal dysplasia (EDA) locus

    SciTech Connect

    Zonana, J.; Jones, M.; Litt, M.; Kramer, P.; Browne, D.; Becker, H.W. ); Brockdorff, N.; Rastan, S. ); Davies, K.P.; Clarke, A. )

    1992-11-01

    The X-linked hypohidrotic ectodermal dysplasia (EDA) locus has been previously localized to the subchromosomal region Xq11-q21.1. The authors have extended previous linkage studies and analyzed linkage between the EDA locus and 10 marker loci, including five new loci, in 41 families. Four of the marker loci showed no recombination with the EDA locus, and six other loci were also linked to the EDA locus with recombination fractions of .009-.075. Multipoint analysis gave support to the placement of the PGK1P1 locus proximal to the EDA locus and the DXS453 and PGK1 loci distal to EDA. Further ordering of the loci could be inferred from a human-rodent somatic cell hybrid derived from an affected female with EDA and an X;9 translocation and from studies of an affected male with EDA and a submicroscopic deletion. Three of the proximal marker loci, which showed no recombination with the EDA locus, when used in combination, were informative in 92% of females. The closely linked flanking polymorphic loci DXS339 and DXS453 had heterozygosites of 72% and 76%, respectively, and when used jointly, they were doubly informative in 52% of females. The human DXS732 locus was defined by a conserved mouse probe pcos169E/4 (DXCrc169 locus) that consegregates with the mouse tabby (Ta) locus, a potential homologue to the EDA locus. The absence of recombination between EDA and the DXSA732 locus lends support to the hypothesis that the DXCrc169 locus in the mouse and the DXS732 locus in humans may contain candidate sequences for the Ta and EDA genes, respectively. 36 refs., 1 fig., 5 tabs.

  19. Rapid Genetic Analysis of X-Linked Chronic Granulomatous Disease by High-Resolution Melting

    PubMed Central

    Hill, Harry R.; Augustine, Nancy H.; Pryor, Robert J.; Reed, Gudrun H.; Bagnato, Joshua D.; Tebo, Anne E.; Bender, Jeffrey M.; Pasi, Brian M.; Chinen, Javier; Hanson, I. Celine; de Boer, Martin; Roos, Dirk; Wittwer, Carl T.

    2010-01-01

    High-resolution melting analysis was applied to X-linked chronic granulomatous disease, a rare disorder resulting from mutations in CYBB. Melting curves of the 13 PCR products bracketing CYBB exons were predicted by Poland's algorithm and compared with observed curves from 96 normal individuals. Primer plates were prepared robotically in batches and dried, greatly simplifying the 3- to 6-hour workflow that included DNA isolation, PCR, melting, and cycle sequencing of any positive products. Small point mutations or insertions/deletions were detected by mixing the hemizygous male DNA with normal male DNA to produce artificial heterozygotes, whereas detection of gross deletions was performed on unmixed samples. Eighteen validation samples and 22 clinical kindreds were analyzed for CYBB mutations. All blinded validation samples were correctly identified. The clinical probands were identified after screening for neutrophil oxidase activity. Nineteen different mutations were found, including seven near intron-exon boundaries predicting splicing defects, five substitutions within exons, three small deletions predicting premature termination, and four gross deletions of multiple exons. Ten novel mutations were found, including (c.) two missense (730T>A, 134T>G), one nonsense (90C>A), four splice site defects (45 + 1G>T, 674 + 4A>G, 1461 + 2delT, and 1462-2A>C), two small deletions (636delT, 1661_1662delCT), and one gross deletion of exons 6 to 8. High-resolution melting can provide timely diagnosis at low cost for effective clinical management of rare, genetic primary immunodeficiency disorders. PMID:20228266

  20. Evidence for X-linked introgression between molecular forms of Anopheles gambiae from Angola.

    PubMed

    Choi, K S; Townson, H

    2012-06-01

    The M and S molecular forms of the African malaria vector Anopheles gambiae (Diptera: Culicidae) are morphologically identical incipient species in which reproductive isolation is incomplete, enabling low-level gene flow between forms. In an attempt to find differences between the M and S forms, sequence variation was studied at loci along the X chromosome in adult female An. gambiae from Angola. A high proportion of M form specimens from Angola (79% of the 456 X chromosomes sampled) were found to contain a 16-bp insertion in intron 4 of the X-linked GPRCCK1 locus, relative to the AgamP3 release of the An. gambiae PEST genome sequence. The insertion was in Hardy-Weinberg equilibrium in Angolan M form populations. The same insertion was found in all S form specimens examined, regardless of where in Africa they were sampled, but was absent from a sample of M form specimens collected in Ghana, Bioko and Mali. In M form specimens from Angola, there was an association between alleles at the GPRCCK1 locus and those at a microsatellite locus, AGXH678, close to the centromere of the X chromosome, with significant linkage disequilibrium between loci separated by 0.472 Mbp (P < 0.033). We show that the insertion results from introgression from the S form into the M form, rather than from the retention of an ancestral character. Gene flow from the S to M form could allow genes of adaptive value to be transferred, including those conferring insecticide resistance and others influencing ecology and behaviour, and thus malaria transmission and control. We discuss factors that may have led to this introgression event.

  1. Phenotypic characterization of X-linked retinoschisis: Clinical, electroretinography, and optical coherence tomography variables

    PubMed Central

    Neriyanuri, Srividya; Dhandayuthapani, Sudha; Arunachalam, Jayamuruga Pandian; Raman, Rajiv

    2016-01-01

    Aims: To study the phenotypic characteristics of X-linked retinoschisis (XLRS) and report the clinical, electroretinogram (ERG), and optical coherence tomography (OCT) variables in Indian eyes. Design: A retrospective study. Materials and Methods: Medical records of 21 patients with retinoschisis who were genetically confirmed to have RS1 mutation were reviewed. The phenotype characterization included the age of onset, best-corrected visual acuity, refractive error, fundus findings, OCT, and ERG. Statistical Analysis Used: Data from both the eyes were used for analysis. A P < 0.05 was set as statistical significance. Data were not normally distributed (P < 0.05, Shapiro wilk); hence, nonparametric tests were used for statistical analysis. Results: All were males whose mean age of presentation was 9 years. Visual acuity was moderately impaired (median 0.6 logMAR, interquartile range: 0.47, 1) in these eyes with a hyperopic refractive error of median +1.75 Ds (interquartile range: +0.50 Ds, +4.25 Ds). About 54.7% of the eyes had both foveal and peripheral schisis, isolated foveal schisis was seen in 28.5% of the eyes, and schisis with retinal detachment was seen in 16.6% of the eyes. The inner nuclear layer was found to be commonly involved in the schisis, followed by outer nuclear and plexiform layers as evident on OCT. On ERG, a- and b-wave amplitudes were significantly reduced in eyes with foveal and peripheral schisis when compared to the eyes with only foveal schisis (P < 0.05). Conclusions: XLRS has phenotypic heterogeneity as evident on OCT, ERG, and clinical findings. PMID:27609164

  2. Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes

    SciTech Connect

    Braun, A.; Ambach, H.; Kammerer, S.; Rolinski, B.; Roscher, A.; Rabl, W.; Stoeckler, S.; Gaertner, J.; Zierz, S.

    1995-04-01

    Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expressions were cerebral childhood ALD, adrenomyecloneuropathy (AMN), and {open_quotes}Addison disease only{close_quotes} (AD) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5{prime} portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. 19 refs., 6 figs., 3 tabs.

  3. Mutational analysis of Btk, the defective gene in X-linked agammaglobulinemia

    SciTech Connect

    Conley, M.E.; Fitch-Hilgenberg, M.E.; Rohrer, J.

    1994-09-01

    Recent studies have shown that X-linked agammaglobulinemia (XLA), a disorder of B cell development, is due to mutations in an scr-like cytoplasmic tyrosine kinase, Btk. Thus far, mutations in this gene have been identified by sequencing of cDNA. To permit the detection of mutations in genomic DNA, we determined the structure of Btk and identified 19 exons in 37 kb of DNA. PCR primers were designed to amplify each exon with its splice sites. Two overlapping PCR products were employed for exons longer than 230 base pairs. Single strand conformation polymorphism (SSCP) analysis was used to screen genomic DNA from 30 unrelated families presumed to carry a mutation in Btk. It was possible to amplify DNA in every reaction from every patient. None of the DNA samples demonstrated more than one aberrant SSCP pattern. Twenty three mutations were detected in 25 families. Seven point mutations resulting in amino acid substitutions were seen. An additional 7 base pair substitutions gave rise to premature stop codons. Two splice defects were noted. Small insertions or deletions, all resulting in frameshifts and premature stop codons were seen in eight patients. One patient had an A to G transition in the ATG start codon. Two mutations, both at CpG dinucleotides, were seen in more than one family. Haplotype analysis, using CA repeats closely linked to Btk, demonstrated that the mutations in these families arose independently. We conclude from these studies that the mutations in Btk in patients with XLA are highly variable. Large deletions are uncommon, although small 1 to 4 bp insertions or deletions constitute as many as one third of the mutations. Further analysis of patients with amino acid substitutions will permit structure/function correlations.

  4. Mutational and protein analysis of patients and heterozygous women with X-linked adrenoleukodystrophy

    SciTech Connect

    Feigenbaum, V.; Guidoux, S.; Aubourg, P.

    1996-06-01

    X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder associated with impaired {beta}-oxidation of very-long-chain fatty acids (VLCFA), is due to mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter (ALD protein [ALDP]). We analyzed the open reading frame of the ALD gene in 44 French ALD kindred by using SSCP or denaturing gradient-gel electrophoresis and studied the effect of mutations on ALDP by immunocytofluorescence and western blotting of fibroblasts and/or white blood cells. Mutations were detected in 37 of 44 kindreds and were distributed over the whole protein-coding region, with the exception of the C terminus encoded in exon 10. Except for two mutations (delAG1801 and P560L) observed four times each, nearly every ALD family has a different mutation. Twenty-four of 37 mutations were missense mutations leading to amino acid changes located in or close to putative transmembrane segments (TMS 2, 3, 4, and 5), in the EAA-like motif and in the nucleotide fold of the ATP-binding domain of ALDP. Of 38 ALD patients tested, 27 (71%) lacked ALDP immunoreactivity in their fibroblasts and/or white blood cells. More than half of missense mutations studied (11 of 21) resulted in a complete lack of ALDP immunoreactivity, and six missense mutations resulted in decreased ALDP expression. The fibroblasts and/or white blood cells of 15 of 15 heterozygous carrier from ALD kindred with no ALDP showed a mixture of positive- and negative-ALDP immunoreactivity due to X-inactivation. Since 5%-15% of heterozygous women have normal VLCFA levels, the immunodetection of ALDP in white blood cells can be applicable in a majority of ALD kindred, to identify heterozygous women, particularly when the ALD gene mutation has not yet been identified. 35 refs., 2 figs., 2 tabs.

  5. X-linked Acrogigantism (X-LAG) Syndrome: Clinical Profile and Therapeutic Responses

    PubMed Central

    Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J.; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H.; Bours, Vincent; Liu, Pengfei; De Herder, Wouter; Pellegata, Natalia; Lupski, James R.; Daly, Adrian F.; Stratakis, Constantine A.

    2015-01-01

    X-linked acro-gigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and a microduplication in chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in 2 families was dominant with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight SDS score of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF-1 and prolactin, usually due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high somatostatin receptor subtype-2 expression in tumor tissue. Postoperative adjuvant pegvisomant achieved control of IGF-1 all 5 cases in which it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID:25712922

  6. Lorenzo's oil and platelet activation in adrenomyeloneuropathy and asymptomatic X-linked adrenoleukodystrophy.

    PubMed

    Konijnenberg, A; van Geel, B M; Sturk, A; Schaap, M C; von dem Borne, A E; de Bruijne-Admiraal, L G; Schutgens, R B; Assies, J; Barth, P G

    1998-01-01

    X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal beta-oxidation, which results in accumulation of very long-chain fatty acids, causing damage to the nervous system, adrenal cortex and testis. The two most frequent phenotypes are childhood cerebral adrenoleukodystrophy (CCALD) and adrenomyeloneuropathy (AMN). Some affected males demonstrate no clinical signs (asymptomatic ALD), whereas female carriers can also be affected. Patients with X-ALD have been treated with Lorenzo's oil, a 4:1 combination of oleic acid and erucic acid, with thrombocytopenia as the main side effect and sometimes leading to a hemorrhagic diathesis. We studied platelet count, size and membrane surface exposure of platelet activation antigens in 17 adult X-ALD patients. Eight patients used the prescribed amount of erucic acid (as glyceroltrierucate) or more (very compliant), five used less(compliant), and four did not use the diet. All eight very compliant patients had highly enlarged platelets and seven manifested thrombocytopenia. An enhanced in vivo platelet activation status was established by increased platelet surface expression of P-selectin (CD62P, PADGEM, GMP-140) in five of the seven thrombocytopenic patients, and of increased fibrinogen receptor exposure (measured with the antibody PAC-1) in three of these five patients. The other nine compliant or untreated patients had normal platelet counts and, generally, normal P-selection and fibrinogen receptor expression. A diet-induced 7- to 27-fold enrichment of erucic acid was observed in the platelets of the four patients studied. We conclude that the thrombocytopenia in AMN patients using Lorenzo'soil is associated with circulating platelets that have an increased erucic acid content, size and activation status. We hypothesize that the erucic acid in some way induces the increased size and thus, directly or indirectly, increased platelet activation or instability in vivo. This then causes the thrombocytopenia

  7. Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy.

    PubMed

    Kemp, Stephan; Valianpour, Fredoen; Denis, Simone; Ofman, Rob; Sanders, Robert-Jan; Mooyer, Petra; Barth, Peter G; Wanders, Ronald J A

    2005-02-01

    X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder characterized by the accumulation of saturated and mono-unsaturated very long-chain fatty acids (VLCFA) and reduced peroxisomal VLCFA beta-oxidation activity. In this study, we investigated the role of VLCFA biosynthesis in X-ALD fibroblasts. Our data demonstrate that elongation of both saturated and mono-unsaturated VLCFAs is enhanced in fibroblasts from patients with peroxisomal beta-oxidation defects including X-ALD, and peroxisome biogenesis disorders. These data indicate that enhanced VLCFA elongation is a general phenomenon associated with an impairment in peroxisomal beta-oxidation, and not specific for X-ALD alone. Analysis of plasma samples from patients with X-ALD and different peroxisomal beta-oxidation deficiencies revealed increased concentrations of VLCFAs up to 32 carbons. We infer that enhanced elongation does not result from impaired peroxisomal beta-oxidation alone, but is due to the additional effect of unchecked chain elongation. We demonstrate that elongated VLCFAs are incorporated into complex lipids. The role of chain elongation was also studied retrospectively in samples from patients with X-ALD previously treated with "Lorenzo's oil." We found that the decrease in plasma C26:0 previously found is offset by the increase of mono-unsaturated VLCFAs, not measured previously during the trial. We conclude that evaluation of treatment protocols for disorders of peroxisomal beta-oxidation making use of plasma samples should include the measurement of saturated and unsaturated VLCFAs of chain lengths above 26 carbon atoms. We also conclude that chain elongation offers an interesting target to be studied as a possible mode of treatment for X-ALD and other peroxisomal beta-oxidation disorders.

  8. 7 Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy

    PubMed Central

    Ratai, Eva; Kok, Trina; Wiggins, Christopher; Wiggins, Graham; Grant, Ellen; Gagoski, Borjan; O'Neill, Gilmore; Adalsteinsson, Elfar; Eichler, Florian

    2010-01-01

    Background Adult patients with X-linked adrenoleukodystrophy (X-ALD) remain at risk for progressive neurological deterioration. Phenotypes vary in their pathology, ranging from axonal degeneration to inflammatory demyelination. The severity of symptoms is poorly explained by conventional imaging. Objective To test the hypothesis that neurochemistry in normal appearing brain differs among adult phenotypes of X-ALD, and that neurochemical changes correlate with the severity of symptoms. Patients and Methods Using a 7 Tesla scanner we performed structural and proton MRSI in 13 adult patients with X-ALD, including 4 patients with adult cerebral ALD (ACALD), 5 with adrenomyeloneuropathy (AMN) and 4 female heterozygotes. Studies were also performed in nine healthy controls. Results Among adult X-ALD phenotypes, MI/Cr was 46% higher and Cho/Cr 21% higher in normal appearing white matter of ACALD compared to AMN (p < 0.05). Both NAA/Cr and Glu/Cr ratios were lower in AMN patients (p = 0.028 and p = 0.036, respectively) than in controls. There were no significant differences between AMN and female heterozygotes. In cortex, ACALD patients had lower values of NAA/Cr compared to female heterozygotes and controls (p = 0.022). The global MI/Cr ratio demonstrated a significant association with the EDSS (Spearman ρ = 0.66, p = 0.039). Conclusion 7 Tesla proton MRSI reveals differences in the neurochemistry of ACALD but is unable to distinguish AMN from female heterozygotes. MI/Cr correlates with the severity of the symptoms and may be a meaningful biomarker in adult X-ALD. PMID:19001168

  9. X-linked cone dystrophy caused by mutation of the red and green cone opsins.

    PubMed

    Gardner, Jessica C; Webb, Tom R; Kanuga, Naheed; Robson, Anthony G; Holder, Graham E; Stockman, Andrew; Ripamonti, Caterina; Ebenezer, Neil D; Ogun, Olufunmilola; Devery, Sophie; Wright, Genevieve A; Maher, Eamonn R; Cheetham, Michael E; Moore, Anthony T; Michaelides, Michel; Hardcastle, Alison J

    2010-07-01

    X-linked cone and cone-rod dystrophies (XLCOD and XLCORD) are a heterogeneous group of progressive disorders that solely or primarily affect cone photoreceptors. Mutations in exon ORF15 of the RPGR gene are the most common underlying cause. In a previous study, we excluded RPGR exon ORF15 in some families with XLCOD. Here, we report genetic mapping of XLCOD to Xq26.1-qter. A significant LOD score was detected with marker DXS8045 (Z(max) = 2.41 [theta = 0.0]). The disease locus encompasses the cone opsin gene array on Xq28. Analysis of the array revealed a missense mutation (c. 529T>C [p. W177R]) in exon 3 of both the long-wavelength-sensitive (LW, red) and medium-wavelength-sensitive (MW, green) cone opsin genes that segregated with disease. Both exon 3 sequences were identical and were derived from the MW gene as a result of gene conversion. The amino acid W177 is highly conserved in visual and nonvisual opsins across species. We show that W177R in MW opsin and the equivalent W161R mutation in rod opsin result in protein misfolding and retention in the endoplasmic reticulum. We also demonstrate that W177R misfolding, unlike the P23H mutation in rod opsin that causes retinitis pigmentosa, is not rescued by treatment with the pharmacological chaperone 9-cis-retinal. Mutations in the LW/MW cone opsin gene array can, therefore, lead to a spectrum of disease, ranging from color blindness to progressive cone dystrophy (XLCOD5). PMID:20579627

  10. DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

    PubMed Central

    Aziz, Azhari; Harrop, Sean P.; Bishop, Naomi E.

    2011-01-01

    Background Autism spectrum disorders (ASDs) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. Methodology/Principal Findings Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. Conclusions/Significance Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation. PMID:21264219

  11. Spontaneous shaker rat mutant – a new model for X-linked tremor/ataxia

    PubMed Central

    Figueroa, Karla P.; Paul, Sharan; Calì, Tito; Lopreiato, Raffaele; Karan, Sukanya; Frizzarin, Martina; Ames, Darren; Zanni, Ginevra; Brini, Marisa; Dansithong, Warunee; Milash, Brett; Scoles, Daniel R.; Carafoli, Ernesto; Pulst, Stefan M.

    2016-01-01

    ABSTRACT The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca2+ transporting, plasma membrane 3 (Atp2b3) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes. PMID:27013529

  12. Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder

    PubMed Central

    Zong, Liang; Guan, Jing; Ealy, Megan; Zhang, Qiujing; Wang, Dayong; Wang, Hongyang; Zhao, Yali; Shen, Zhirong; Campbell, Colleen A; Wang, Fengchao; Yang, Ju; Sun, Wei; Lan, Lan; Ding, Dalian; Xie, Linyi; Qi, Yue; Lou, Xin; Huang, Xusheng; Shi, Qiang; Chang, Suhua; Xiong, Wenping; Yin, Zifang; Yu, Ning; Zhao, Hui; Wang, Jun; Wang, Jing; Salvi, Richard J; Petit, Christine; Smith, Richard J H; Wang, Qiuju

    2015-01-01

    Background Auditory neuropathy spectrum disorder (ANSD) is a form of hearing loss in which auditory signal transmission from the inner ear to the auditory nerve and brain stem is distorted, giving rise to speech perception difficulties beyond that expected for the observed degree of hearing loss. For many cases of ANSD, the underlying molecular pathology and the site of lesion remain unclear. The X-linked form of the condition, AUNX1, has been mapped to Xq23-q27.3, although the causative gene has yet to be identified. Methods We performed whole-exome sequencing on DNA samples from the AUNX1 family and another small phenotypically similar but unrelated ANSD family. Results We identified two missense mutations in AIFM1 in these families: c.1352G>A (p.R451Q) in the AUNX1 family and c.1030C>T (p.L344F) in the second ANSD family. Mutation screening in a large cohort of 3 additional unrelated families and 93 sporadic cases with ANSD identified 9 more missense mutations in AIFM1. Bioinformatics analysis and expression studies support this gene as being causative of ANSD. Conclusions Variants in AIFM1 gene are a common cause of familial and sporadic ANSD and provide insight into the expanded spectrum of AIFM1-associated diseases. The finding of cochlear nerve hypoplasia in some patients was AIFM1-related ANSD implies that MRI may be of value in localising the site of lesion and suggests that cochlea implantation in these patients may have limited success. PMID:25986071

  13. Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus

    SciTech Connect

    Bichet, D.G.; Lonergan, M.; Arthus, M.F. ); Goodyer, P. ); Birnbaumer, M.; Rosenthal, W. ); Nivet, H.; Benoit, S.; Giampietro, P.; Simonetti, S.

    1994-08-01

    X-linked nephrogenic diabetes insipidus (NDI) is a rare disease with defective renal and extrarenal arginine-vasopressin V[sub 2] receptor responses due to mutations in the AVPR2 gene in Xq28. The authors analyzed 31 independent NDI families to determine the nature and recurrence of AVPR2 mutations. Twenty-one new putative disease-causing mutations were identified: 113delCT, 253del35, 255del9, 274insG, V88M, R106C, 402delCT, C112R, Y124X, S126F, W164S, S167L, 684delTA, 804insG, W284X, A285P, W293X, R337X, and three large deletions or gene rearrangements. Five other mutations - R113W, Y128S, R137H, R181C, and R202C - that previously had been reported in other families were detected. There was evidence for recurrent mutation for four mutations (R113W, R137H, S167L, and R337X). Eight de novo mutation events were detected (274insG, R106C, Y128S, 167L [twice], R202C, 684delTA, and R337X). The origins were maternal (one), grandmaternal (one), and grandpaternal (six). In the 31 NDI families and 6 families previously reported, there is evidence both for mutation hot spots for nucleotide substitutions and for small deletions and insertions. More than half (58%) of the nucleotide substitutions in 26 families could be a consequence of 5-methyl-cytosine deamination at a CpG dinucleotide. Most of the small deletions and insertions could be attributed to slipped mispairing during DNA replication. 25 refs., 2 figs., 2 tabs.

  14. Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets

    SciTech Connect

    Kang, Qing-lin; Xu, Jia; Zhang, Zeng; He, Jin-wei; Lu, Lian-song; Fu, Wen-zhen; Zhang, Zhen-lin

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer In our study, all of the patients were of Han Chinese ethnicity, which were rarely reported. Black-Right-Pointing-Pointer We identified three novel PHEX gene mutations in four unrelated families with XLH. Black-Right-Pointing-Pointer We found that the relationship between the phenotype and genotype of the PHEX gene was not invariant. Black-Right-Pointing-Pointer We found that two PHEX gene sites, p.534 and p.731, were conserved. -- Abstract: Background: X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related gene with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH. Methods: We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously. Results: Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A > T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T > C in exon 22, resulting in p.F731S. Conclusions: We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH.

  15. Molecular population genetics of X-linked genes in Drosophila pseudoobscura.

    PubMed

    Kovacevic, M; Schaeffer, S W

    2000-09-01

    This article presents a nucleotide sequence analysis of 500 bp determined in each of five X-linked genes, runt, sisterlessA, period, esterase 5, and Heat-shock protein 83, in 40 Drosophila pseudoobscura strains collected from two populations. Estimates of the neutral migration parameter for the five loci show that gene flow among D. pseudoobscura populations is sufficient to homogenize inversion frequencies across the range of the species. Nucleotide diversity at each locus fails to reject a neutral model of molecular evolution. The sample of 40 chromosomes included six Sex-ratio inversions, a series of three nonoverlapping inversions that are associated with a strong meiotic drive phenotype. The selection driven by the Sex-ratio meiotic drive element has not fixed variation across the X chromosome of D. pseudoobscura because, while significant linkage disequilibrium was observed within the sisterlessA, period, and esterase 5 genes, we did not find evidence for nonrandom association among loci. The Sex-ratio chromosome was estimated to be 25,000 years old based on the decomposition of linkage disequilibrium between esterase 5 and Heat-shock protein 83 or 1 million years old based on the net divergence of esterase 5 between Standard and Sex-ratio chromosomes. Genetic diversity was depressed within esterase 5 within Sex-ratio chromosomes, while the four other genes failed to show a reduction in heterozygosity in the Sex-ratio background. The reduced heterogeneity in esterase 5 is due either to its location near one of the Sex-ratio inversion breakpoints or that it is closely linked to a gene or genes responsible for the Sex-ratio meiotic drive system.

  16. A Modified γ-Retrovirus Vector for X-Linked Severe Combined Immunodeficiency

    PubMed Central

    Hacein-Bey-Abina, S.; Pai, S.-Y.; Gaspar, H.B.; Armant, M.; Berry, C.C.; Blanche, S.; Bleesing, J.; Blondeau, J.; de Boer, H.; Buckland, K.F.; Caccavelli, L.; Cros, G.; De Oliveira, S.; Fernández, K.S.; Guo, D.; Harris, C.E.; Hopkins, G.; Lehmann, L.E.; Lim, A.; London, W.B.; van der Loo, J.C.M.; Malani, N.; Male, F.; Malik, P.; Marinovic, M.A.; McNicol, A.-M.; Moshous, D.; Neven, B.; Oleastro, M.; Picard, C.; Ritz, J.; Rivat, C.; Schambach, A.; Shaw, K.L.; Sherman, E.A.; Silberstein, L.E.; Six, E.; Touzot, F.; Tsytsykova, A.; Xu-Bayford, J.; Baum, C.; Bushman, F.D.; Fischer, A.; Kohn, D.B.; Filipovich, A.H.; Notarangelo, L.D.; Cavazzana, M.; Williams, D.A.; Thrasher, A.J.

    2014-01-01

    BACKGROUND In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus–based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS All patients received bone marrow–derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2 , MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.) PMID:25295500

  17. Clinical presentations of X-linked retinoschisis in Taiwanese patients confirmed with genetic sequencing

    PubMed Central

    Liu, Laura; Chen, Ho-Min; Tsai, Shawn; Chang, Tsong-Chi; Tsai, Tzu-Hsun; Yang, Chung-May; Chao, An-Ning; Chen, Kuan-Jen; Kao, Ling-Yuh; Yeung, Ling; Yeh, Lung-Kun; Hwang, Yih-Shiou; Wu, Wei-Chi; Lai, Chi-Chun

    2015-01-01

    Purpose To investigate the clinical characteristics of X-linked retinoschisis (XLRS) and identify genetic mutations in Taiwanese patients with XLRS. Methods This study included 23 affected males from 16 families with XLRS. Fundus photography, spectral domain optical coherent tomography (SD-OCT), fundus autofluorescence (FAF), and full-field electroretinograms (ERGs) were performed. The coding regions of the RS1 gene that encodes retinoschisin were sequenced. Results The median age at diagnosis was 18 years (range 4–58 years). The best-corrected visual acuity ranged from no light perception to 20/25. The typical spoke-wheel pattern in the macula was present in 61% of the patients (14/23) while peripheral retinoschisis was present in 43% of the patients (10/23). Four eyes presented with vitreous hemorrhage, and two eyes presented with leukocoria that mimics Coats’ disease. Macular schisis was identified with SD-OCT in 82% of the eyes (31/38) while foveal atrophy was present in 18% of the eyes (7/38). Concentric area of high intensity was the most common FAF abnormality observed. Seven out of 12 patients (58%) showed electronegative ERG findings. Sequencing of the RS1 gene identified nine mutations, six of which were novel. The mutations are all located in exons 4–6, including six missense mutations, two nonsense mutations, and one deletion-caused frameshift mutation. Conclusions XLRS is a clinically heterogeneous disease with profound phenotypic inter- and intrafamiliar variability. Genetic sequencing is valuable as it allows a definite diagnosis of XLRS to be made without the classical clinical features and ERG findings. This study showed the variety of clinical features of XLRS and reported novel mutations. PMID:25999676

  18. Response to Drs. Shastry and Trese: Phenotype-genotype correlations in X-linked retinitis pigmentosa

    SciTech Connect

    Kaplan, J.; Munnich, A.

    1996-11-11

    Shastry and Trese recently reported on a large kindred with X-linked retinitis pigmentosa (XLRP) characterized by a loss of central vision and preserved peripheral function. In their report, the disease had an early onset with severe myopia and a loss of central vision, while night blindness occurred later. Genetic analysis suggested that the disease was linked to the RP2 locus, and the authors raised the question of whether other cases linked to RP2 could display a similar loss of central vision. Three years ago, we reported on 4 large XLRP pedigrees with a very early onset with severe myopia and early loss of visual acuity, while in 5 other families the disease started later with night blindness. We showed that the first clinical form was linked to RP2, while the second was linked to RP3. Thus, the major difference between the two forms concerns the initial symptom, information which can be obtained from the parents and patients after careful questioning. By contrast, in adult life, no difference in either severity of disease or aspect of the fundus was observed in our series, regardless of the clinical subtype of XLRP. Some months later, Jacobson et al. reported on a pedigree with an RP2 genotype, and their data support the notion that in XLRP of RP2 type 1, cone dysfunction takes place first, and as the disease advances both rods and cones are affected. We were very happy, therefore, to read that the study of Shastry and Trese fully confirmed our previous findings. 3 refs.

  19. Deletion pattern of the STS gene in X-linked ichthyosis in a Mexican population.

    PubMed Central

    Jimenez Vaca, A. L.; Valdes-Flores, M. del R.; Rivera-Vega, M. R.; González-Huerta, L. M.; Kofman-Alfaro, S. H.; Cuevas-Covarrubias, S. A.

    2001-01-01

    BACKGROUND: X-linked ichthyosis (XLI) is an inherited disorder due to steroid sulfatase deficiency (STS). Most XLI patients (>90%) have complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats (G1.3 and CRI-S232) on either side of the STS gene seems to play a role in the high frequency of these interstitial deletions. In the present study, we analyzed 80 Mexican patients with XLI and complete deletion of the STS gene. MATERIALS AND METHODS: STS activity was measured in the leukocytes using 7-[(3)H]-dehydroepiandrosterone sulfate as a substrate. Amplification of the regions telomeric-DXS89, DXS996, DXS1139, DXS1130, 5' STS, 3' STS, DXS1131, DXS1133, DXS237, DXS1132, DXF22S1, DXS278, DXS1134-centromeric was performed through PCR. RESULTS: No STS activity was detected in the XLI patients (0.00 pmoles/mg protein/h). We observed 3 different patterns of deletion. The first two groups included 25 and 32 patients, respectively, in which homologous sequences were involved. These subjects showed the 5' STS deletion at the sequence DXS1139, corresponding to the probe CRI-S232A2. The group of 32 patients presented the 3' STS rupture site at the sequence DXF22S1 (probe G1.3) and the remaining 25 patients had the 3' STS breakpoint at the sequence DXS278 (probe CRI-S232B2). The third group included 23 patients with the breakpoints at several regions on either side of the STS gene. No implication of the homologous sequences were observed in this group. CONCLUSION: These data indicate that more complex mechanisms, apart from homologous recombination, are occurring in the genesis of the breakpoints of the STS gene of XLI Mexican patients. PMID:11844872

  20. A candidate gene for X-linked Ocular Albinism (OA1)

    SciTech Connect

    Bassi, M.T.; Schiaffino, V.; Rugarli, E.

    1994-09-01

    Ocular Albinism of the Nettleship-Fall type 1 (OA1) is the most common form of ocular albinism. It is transmitted as an X-linked recessive trait with affected males showing severe reduction of visual acuity, nystagmus, strabismus, photophobia. Ophthalmologic examination reveals foveal hypoplasia, hypopigmentation of the retina and iris translucency. Microscopic examination of melanocytes suggests that the underlying defect in OA1 is an abnormality in melanosome formation. Recently we assembled a 350 kb cosmid contig spanning the entire critical region on Xp22.3, which measures approximately 110 kb. A minimum set of cosmids was used to identify transcribed sequences using both cDNA selection and exon amplification. Two putative exons recovered by exon amplification strategy were found to be highly conserved throughout evolution and, therefore, they were used as probes for the screening of fetal and adult retina cDNA libraries. This led to the isolation of clones spanning a full-length cDNA which measures 7.6 kb. Sequence analysis revealed that the predicted protein product shows homology with syntrophines and a Xenopus laevis apical protein. The gene covers approximately 170 kb of DNA and spans the entire critical region for OA1, being deleted in two patients with contiguous gene deletion including OA1 and in one patient with isolated OA1. Therefore, this new gene represents a very strong candidate for involvement in OA1 (an alternative, but unlikely possibility to be considered is that the true OA1 gene lies within an intron of the former). Northern analysis revealed very high level of expression in retina and melanoma. Unlike most Xp22.3 genes, this gene is conserved in the mouse. We are currently performing SSCP analysis and direct sequencing of exons on DNAs from approximately 60 unrelated patients with OA1 for mutation detection.

  1. Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.

    PubMed

    Daly, Adrian F; Yuan, Bo; Fina, Frederic; Caberg, Jean-Hubert; Trivellin, Giampaolo; Rostomyan, Liliya; de Herder, Wouter W; Naves, Luciana A; Metzger, Daniel; Cuny, Thomas; Rabl, Wolfgang; Shah, Nalini; Jaffrain-Rea, Marie-Lise; Zatelli, Maria Chiara; Faucz, Fabio R; Castermans, Emilie; Nanni-Metellus, Isabelle; Lodish, Maya; Muhammad, Ammar; Palmeira, Leonor; Potorac, Iulia; Mantovani, Giovanna; Neggers, Sebastian J; Klein, Marc; Barlier, Anne; Liu, Pengfei; Ouafik, L'Houcine; Bours, Vincent; Lupski, James R; Stratakis, Constantine A; Beckers, Albert

    2016-04-01

    Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes. PMID:26935837

  2. Somatic GPR101 Duplication Causing X-Linked Acrogigantism (XLAG)—Diagnosis and Management

    PubMed Central

    Rodd, Celia; Millette, Maude; Iacovazzo, Donato; Stiles, Craig E.; Barry, Sayka; Evanson, Jane; Albrecht, Steffen; Caswell, Richard; Bunce, Benjamin; Jose, Sian; Trouillas, Jacqueline; Roncaroli, Federico; Sampson, Julian; Ellard, Sian

    2016-01-01

    Context: Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) with a female preponderance. Case Description: A 4-year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 μg/L; normal, <18 μg/L), IGF-1 (745 μg/L; normal, 64–369 μg/L), and fasting GH > 35.0 μg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 × 15 × 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality. Conclusions: Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary. PMID:26982009

  3. Canine epilepsy genetics.

    PubMed

    Ekenstedt, Kari J; Patterson, Edward E; Mickelson, James R

    2012-02-01

    There has been much interest in utilizing the dog as a genetic model for common human diseases. Both dogs and humans suffer from naturally occurring epilepsies that share many clinical characteristics. Investigations of inherited human epilepsies have led to the discovery of several mutated genes involved in this disease; however, the vast majority of human epilepsies remain unexplained. Mouse models of epilepsy exist, including single-gene spontaneous and knockout models, but, similar to humans, other, polygenic models have been more difficult to discern. This appears to also be the case in canine epilepsy genetics. There are two forms of canine epilepsies for which gene mutations have been described to date: the progressive myoclonic epilepsies (PMEs) and idiopathic epilepsy (IE). Gene discovery in the PMEs has been more successful, with eight known genes; six of these are orthologous to corresponding human disorders, while two are novel genes that can now be used as candidates for human studies. Only one IE gene has been described in dogs, an LGI2 mutation in Lagotto Romagnolos with a focal, juvenile remitting epilepsy. This gene is also a novel candidate for human remitting childhood epilepsy studies. The majority of studies of dog breeds with IE, however, have either failed to identify any genes or loci of interest, or, as in complex mouse and human IEs, have identified multiple QTLs. There is still tremendous promise in the ongoing canine epilepsy studies, but if canine IEs prove to be as genetically complex as human and murine IEs, then deciphering the bases of these canine epilepsies will continue to be challenging.

  4. Vaccines for Canine Leishmaniasis

    PubMed Central

    Palatnik-de-Sousa, Clarisa B.

    2012-01-01

    Leishmaniasis is the third most important vector-borne disease worldwide. Visceral leishmaniasis (VL) is a severe and frequently lethal protozoan disease of increasing incidence and severity due to infected human and dog migration, new geographical distribution of the insect due to global warming, coinfection with immunosuppressive diseases, and poverty. The disease is an anthroponosis in India and Central Africa and a canid zoonosis (ZVL) in the Americas, the Middle East, Central Asia, China, and the Mediterranean. The ZVL epidemic has been controlled by one or more measures including the culling of infected dogs, treatment of human cases, and insecticidal treatment of homes and dogs. However, the use of vaccines is considered the most cost–effective control tool for human and canine disease. Since the severity of the disease is related to the generation of T-cell immunosuppression, effective vaccines should be capable of sustaining or enhancing the T-cell immunity. In this review we summarize the clinical and parasitological characteristics of ZVL with special focus on the cellular and humoral canine immune response and review state-of-the-art vaccine development against human and canine VL. Experimental vaccination against leishmaniasis has evolved from the practice of leishmanization with living parasites to vaccination with crude lysates, native parasite extracts to recombinant and DNA vaccination. Although more than 30 defined vaccines have been studied in laboratory models no human formulation has been licensed so far; however three second-generation canine vaccines have already been registered. As expected for a zoonotic disease, the recent preventive vaccination of dogs in Brazil has led to a reduction in the incidence of canine and human disease. The recent identification of several Leishmania proteins with T-cell epitopes anticipates development of a multiprotein vaccine that will be capable of protecting both humans and dogs against VL. PMID:22566950

  5. Intra-amniotic rAAV-mediated microdystrophin gene transfer improves canine X-linked muscular dystrophy and may induce immune tolerance.

    PubMed

    Hayashita-Kinoh, Hiromi; Yugeta, Naoko; Okada, Hironori; Nitahara-Kasahara, Yuko; Chiyo, Tomoko; Okada, Takashi; Takeda, Shin'ichi

    2015-04-01

    Duchenne muscular dystrophy (DMD) is a severe congenital disease due to mutations in the dystrophin gene. Supplementation of dystrophin using recombinant adenoassociated virus vector has promise as a treatment of DMD, although therapeutic benefit of the truncated dystrophin still remains to be elucidated. Besides, host immune responses against the vector as well as transgene products have been denoted in the clinical gene therapy studies. Here, we transduced dystrophic dogs fetuses to investigate the therapeutic effects of an AAV vector expressing microdystrophin under conditions of immune tolerance. rAAV-CMV-microdystrophin and a rAAV-CAG-luciferase were injected into the amniotic fluid surrounding fetuses. We also reinjected rAAV9-CMV-microdystrophin into the jugular vein of an infant dystrophic dog to induce systemic expression of microdystrophin. Gait and cardiac function significantly improved in the rAAV-microdystrophin-injected dystrophic dog, suggesting that an adequate treatment of rAAV-microdystrophin with immune modulation induces successful long-term transgene expression to analyze improved dystrophic phenotype.

  6. Intra-Amniotic rAAV-Mediated Microdystrophin Gene Transfer Improves Canine X-Linked Muscular Dystrophy and May Induce Immune Tolerance

    PubMed Central

    Hayashita-Kinoh, Hiromi; Yugeta, Naoko; Okada, Hironori; Nitahara-Kasahara, Yuko; Chiyo, Tomoko; Okada, Takashi; Takeda, Shin'ichi

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a severe congenital disease due to mutations in the dystrophin gene. Supplementation of dystrophin using recombinant adenoassociated virus vector has promise as a treatment of DMD, although therapeutic benefit of the truncated dystrophin still remains to be elucidated. Besides, host immune responses against the vector as well as transgene products have been denoted in the clinical gene therapy studies. Here, we transduced dystrophic dogs fetuses to investigate the therapeutic effects of an AAV vector expressing microdystrophin under conditions of immune tolerance. rAAV-CMV-microdystrophin and a rAAV-CAG-luciferase were injected into the amniotic fluid surrounding fetuses. We also reinjected rAAV9-CMV-microdystrophin into the jugular vein of an infant dystrophic dog to induce systemic expression of microdystrophin. Gait and cardiac function significantly improved in the rAAV-microdystrophin-injected dystrophic dog, suggesting that an adequate treatment of rAAV-microdystrophin with immune modulation induces successful long-term transgene expression to analyze improved dystrophic phenotype. PMID:25586688

  7. Linkage analysis and physical mapping near the gene for x-linked agammaglobulinemia at Xq22

    SciTech Connect

    Parolini, O.; Lassiter, G.L.; Henry, M.J.; Conley, M.E. St. Jude Children's Research Hospital, Memphis, TN ); Hejtmancik, J.F. ); Allen, R.C.; Belmont, J.W. ); Barker, D.F. )

    1993-02-01

    The gene for x-linked agammaglobulinemia (XLA) has been mapped to Xq22. No recombinations have been reported between the gene and the prob p212 at DXS178; however, this probe is informative in only 30-40% of women and the reported flanking markers, DXS3 and DXS94, and 10-15 cM apart. To identify additional probes that might be useful in genetic counseling, we examined 11 polymorphisms that have been mapped to the Xq21.3-q22 region in 13 families with XLA. In addition, pulsed-field gel electrophoresis and yeast artificial chromosomes (YACs) were used to further characterize the segman of DNA within which the gene for SLA must lie. The results demonstrated that DXS366 and DXS442, which share a 430-kb pulsed-field fragment, could replace DXS3 as proximal flanking markers. Probes at DXS178 and DXS265 identified the same 145-kb pulsed-field fragment, and both loci were contained within a 200-kb YAC identified with the probe p212. A highly polymorphic CA repeat (DCS178CA) was isolated from one end of this YAC and used in linkage analysis. Probes at DXS101 and DXS328 shared several pulsed-field fragments, the smallest of which was 250 kb. No recombinations were seen between XLA and the DXS178-DXS265-DXS178CA complex, DXS101, DXS328, DXS87, or the gene for proteolipid protein (PLP). Key crossovers, when combined with the linkage data from families with Alport syndrome, suggested the following order of loci: cen-DXS3-DXS366-DXS442-(PLP, DXS101, DXS328, DXS178-DXS265-DXS178CA complex, XL)-(DXS87, DXS94)-DXS327-(DXS350, DXS362)-tel. Our studies also limit the segment of DNA within which the XLA gene must lie to the 3- to 4-cM distance between DCS442 and DXS94 and they identify and orient polymorphisms that can be used in genetic counseling not only for XLA but also for Pelizaeus-Merzbacher disease (PLP deficiency), Alport syndrome (COL4A5 deficiency), and Fabry disease ([alpha]-galactosidase A difficiency). 31 refs., 5 figs., 2 tabs.

  8. Lovastatin therapy for X-linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients.

    PubMed

    Pai, G S; Khan, M; Barbosa, E; Key, L L; Craver, J R; Curé, J K; Betros, R; Singh, I

    2000-04-01

    X-linked adrenoleukodystrophy (X-ALD) is a progressive demyelinating disorder whose neurological signs and symptoms can manifest in childhood as cerebral ALD or in adulthood in the form of a progressive myelopathy (AMN). The consistent metabolic abnormality in all forms of X-ALD is an inherited defect in the peroxisomal beta-oxidation of very long chain (VLC) fatty acids (>C(22:0)) which may in turn lead to a neuroinflammatory process associated with demyelination of the cerebral white matter. The current treatment for X-ALD with Lorenzo's oil aims to lower the excessive quantities of VLC fatty acids that accumulate in the patients' plasma and tissues, but does not directly address the inflammatory process in X-ALD. We have previously demonstrated that lovastatin and other 3-HMG-CoA reductase inhibitors are capable of normalizing VLC fatty acid levels in primary skin fibroblasts derived from X-ALD patients. Lovastatin can block the induction of inducible nitric oxide synthase and proinflammatory cytokines in astrocytes, microglia, and macrophages in vitro. In a preliminary report, we demonstrated that lovastatin therapy can normalize VLC fatty acids in the plasma of patients with X-ALD. Here we report our clinical and biochemical observations on 12 patients with X-ALD who were treated with lovastatin for up to 12 months. Our results show that the high plasma levels of hexacosanoic acid (C(26:0)) showed a decline from pretreatment values within 1 to 3 months of starting therapy with 40 mg of lovastatin per day and stabilized at various levels during a period of observation up to 12 months. The percentage decline from pretreatment values varied and did not correlate with the type of ALD gene mutation (point mutation versus gene deletion). In 6 patients, in whom red cell membrane fatty acid composition was studied, a mean correction of 50% of the excess C(26:0) was observed after 6 months of therapy suggesting sustained benefit. In a few patients who discontinued

  9. New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome

    SciTech Connect

    Jouet, M.; Kenwick, S.; Moncla, A.

    1995-06-01

    The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function. 39 refs., 5 figs., 3 tabs.

  10. Elevated urinary β2 microglobulin in the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy.

    PubMed

    Kurashige, Takashi; Takahashi, Tetsuya; Yamazaki, Yu; Nagano, Yoshito; Kondo, Keita; Nakamura, Takeshi; Yamawaki, Takemori; Tsuburaya, Rie; Hayashi, Yukiko K; Nonaka, Ikuya; Nishino, Ichizo; Matsumoto, Masayasu

    2013-11-01

    Here we report what is to our knowledge the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. The index case is a 52-year-old man with almost 40years of progressive proximal muscle weakness. High urinary β2 microglobulin, normal serum β2 microglobulin, autophagic vacuoles with sarcolemmal features, and a hemizygous c.164-7T>G mutation in the VMA21 gene were found. His two maternal uncles had similar clinicopathological findings. High urinary β2 microglobulin without obvious renal dysfunction might result from decreased urine acidification in the distal convoluted tubules caused by the VMA21 gene mutation. These findings might prove to be useful as a preliminary marker suggestive of X-linked myopathy with excessive autophagy.

  11. Impacted Canines: Our Clinical Experience

    PubMed Central

    Chawla, Sonia; Marya, Karan; Jhamb, Aakarsh; Bhatia, Hind Pal

    2011-01-01

    Background To discuss the management of impacted canines and the various approaches used for the same. Materials and methods The data of 33 cases, with 43 impacted canine teeth, seen and operated over a period of 3-year in Santosh Dental College and Hospital has been compiled. The diagnostic methods and treatment modalities undertaken are described and discussed. Results Canine impactions were more common in the maxilla as compared with mandible in our study, which was statistically significant. Impacted canine position was mostly palatal in maxilla and labial in mandible. Chi-square test yielded a p-value of 0.002 which shows that there is an association between arch and position. The treatment options used were surgical exposure and orthodontic repositioning, cyst enucleation with extraction of impacted canine and surgical removal of impacted canine. Conclusion Surgical exposure and orthodontic repositioning was successfully applied as first-line treatment for correcting ectopic positioned canine. In cases where exposure and subsequent orthodontic treatment was not indicated, the impacted canine was surgically removed to prevent future problems and surgical procedure was designed according to position of impacted canine.

  12. Central precocious puberty in a patient with X-linked adrenal hypoplasia congenita and Xp21 contiguous gene deletion syndrome.

    PubMed

    Koh, Ji Won; Kang, So Young; Kim, Gu Hwan; Yoo, Han Wook; Yu, Jeesuk

    2013-06-01

    X-linked adrenal hypoplasia congenita is caused by the mutation of DAX-1 gene (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), and can occur as part of a contiguous gene deletion syndrome in association with glycerol kinase (GK) deficiency, Duchenne muscular dystrophy and X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene deficiency. It is usually associated with hypogonadotropic hypogonadism, although in rare cases, it has been reported to occur in normal puberty or even central precocious puberty. This study addresses a case in which central precocious puberty developed in a boy with X-linked adrenal hypoplasia congenita who had complete deletion of the genes DAX-1, GK and IL1RAPL1 (Xp21 contiguous gene deletion syndrome). Initially he was admitted for the management of adrenal crisis at the age of 2 months, and managed with hydrocortisone and florinef. At 45 months of age, his each testicular volumes of 4 mL and a penile length of 5 cm were noted, with pubic hair of Tanner stage 2. His bone age was advanced and a gonadotropin-releasing hormone (GnRH) stimulation test showed a luteinizing hormone peak of 8.26 IU/L, confirming central precocious puberty. He was then treated with a GnRH agonist, as well as steroid replacement therapy. In Korea, this is the first case of central precocious puberty developed in a male patient with X-linked adrenal hypoplasia congenita. PMID:24904859

  13. [Alignment of malpositioned canines].

    PubMed

    Wagner, L

    1991-03-01

    This article presents a system for aligning impacted canines. The base of this system is the lingual arch, a rigid reaction unit of four teeth, molars and premolars. From this base unit an impacted canine can be extruded, moved distally, jumped over the occlusion and derotated by segment arches, coil springs and elastic ligatures. The efficiency of this appliance is due to the elimination of undesired reactive forces, the safe moving of teeth, the possibility of an exact force application and the simple manipulation; also the esthetic inconvenience is minimal. All this results in a better prognosis and an essentially shorter treatment time. This appliance can be used in the upper and the lower jaw. Schematic drawings and clinical examples demonstrate this method.

  14. Complete deletion of the proteolipid protein gene (PLP) in a family with X-linked Pelizaeus-Merzbacher disease.

    PubMed Central

    Raskind, W H; Williams, C A; Hudson, L D; Bird, T D

    1991-01-01

    Pelizaeus-Merzbacher disease (PMD) is an X-linked neurologic disorder characterized by dysmyelination in the central nervous system. Proteolipid protein (PLP), a major structural protein of myelin, is coded on the X chromosome. It has been postulated that a defect in the PLP gene is responsible for PMD. Different single-nucleotide substitutions have been found in conserved regions of the PLP gene of four unrelated PMD patients. Novel Southern blot patterns suggested a complex rearrangement in a fifth family. Linkage to PLP has been shown in others. We evaluated the PLP locus in a four-generation family with two living males affected with X-linked PMD. Analysis of DNA from the affected males revealed complete absence of a band, with PLP probes encompassing the promoter region, the entire coding region, and the 3' untranslated region and spanning at least 29 kb of genomic DNA. DNA from unaffected relatives gave the expected band pattern. Two obligate and one probable carrier women were hemizygous for the PLP locus by dosage analysis. Although it is unlikely, the previously described point mutations in PLP could represent polymorphisms. The finding of complete deletion of the PLP gene in our family is a stronger argument that mutations in PLP are responsible for X-linked PMD. Images Figure 3 PMID:1720927

  15. Variation in the X-Linked EFHC2 Gene Is Associated with Social Cognitive Abilities in Males

    PubMed Central

    Startin, Carla M.; Fiorentini, Chiara; de Haan, Michelle; Skuse, David H.

    2015-01-01

    Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males. PMID:26107779

  16. Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy.

    PubMed Central

    Chen, W W; Watkins, P A; Osumi, T; Hashimoto, T; Moser, H W

    1987-01-01

    Very long chain fatty acids, which accumulate in plasma and tissues in X-linked adrenoleukodystrophy (ALD), neonatal ALD, and the Zellweger cerebrohepatorenal syndrome, are degraded by the peroxisomal beta-oxidation pathway, consisting of acyl-CoA oxidase, the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, and beta-ketothiolase. A marked deficiency of all three enzyme proteins was reported in livers from patients with the Zellweger syndrome, a disorder in which peroxisomes are decreased or absent. Peroxisomes are not as markedly decreased in neonatal ALD and appear normal in X-linked ALD. Immunoblot analysis of the peroxisomal beta-oxidation enzymes revealed an almost complete lack of the bifunctional enzyme in neonatal ALD liver, similar to the finding in Zellweger tissue. In contrast, acyl-CoA oxidase and beta-ketothiolase were present in neonatal ALD liver, although the thiolase appeared to be in precursor form (2-3 kDa larger than the mature enzyme) in neonatal ALD. Unlike either neonatal ALD or Zellweger syndrome, all three peroxisomal beta-oxidation enzymes were present in X-linked ALD liver. Despite the absence in neonatal ALD liver of bifunctional enzyme protein, its mRNA was detected by RNA blot analysis in fibroblasts from these patients. These observations suggest that lack of bifunctional enzyme protein in neonatal ALD results from either abnormal translation of the mRNA or degradation of the enzyme prior to its entry into peroxisomes. Images PMID:3469675

  17. A complex genetic basis to X-linked hybrid male sterility between two species of house mice.

    PubMed

    Good, Jeffrey M; Dean, Matthew D; Nachman, Michael W

    2008-08-01

    The X chromosome plays a central role in the evolution of reproductive isolation, but few studies have examined the genetic basis of X-linked incompatibilities during the early stages of speciation. We report the results of a large experiment focused on the reciprocal introgression of the X chromosome between two species of house mice, Mus musculus and M. domesticus. Introgression of the M. musculus X chromosome into a wild-derived M. domesticus genetic background produced male-limited sterility, qualitatively consistent with previous experiments using classic inbred strains to represent M. domesticus. The genetic basis of sterility involved a minimum of four X-linked factors. The phenotypic effects of major sterility QTL were largely additive and resulted in complete sterility when combined. No sterility factors were uncovered on the M. domesticus X chromosome. Overall, these results revealed a complex and asymmetric genetic basis to X-linked hybrid male sterility during the early stages of speciation in mice. Combined with data from previous studies, we identify one relatively narrow interval on the M. musculus X chromosome involved in hybrid male sterility. Only a handful of spermatogenic genes are within this region, including one of the most rapidly evolving genes on the mouse X chromosome.

  18. Evidence for increased SOX3 dosage as a risk factor for X-linked hypopituitarism and neural tube defects.

    PubMed

    Bauters, Marijke; Frints, Suzanna G; Van Esch, Hilde; Spruijt, Liesbeth; Baldewijns, Marcella M; de Die-Smulders, Christine E M; Fryns, Jean-Pierre; Marynen, Peter; Froyen, Guy

    2014-08-01

    Genomic duplications of varying lengths at Xq26-q27 involving SOX3 have been described in families with X-linked hypopituitarism. Using array-CGH we detected a 1.1 Mb microduplication at Xq27 in a large family with three males suffering from X-linked hypopituitarism. The duplication was mapped from 138.7 to 139.8 Mb, harboring only two annotated genes, SOX3 and ATP11C, and was shown to be a direct tandem copy number gain. Unexpectedly, the microduplication did not fully segregate with the disease in this family suggesting that SOX3 duplications have variable penetrance for X-linked hypopituitarism. In the same family, a female fetus presenting with a neural tube defect was also shown to carry the SOX3 copy number gain. Since we also demonstrated increased SOX3 mRNA levels in amnion cells derived from an unrelated t(X;22)(q27;q11) female fetus with spina bifida, we propose that increased levels of SOX3 could be a risk factor for neural tube defects.

  19. A New Chromosome X Exon-Specific Microarray Platform for Screening of Patients with X-Linked Disorders

    PubMed Central

    Bashiardes, Stavros; Kousoulidou, Ludmila; van Bokhoven, Hans; Ropers, Hans-Hilger; Chelly, Jamel; Moraine, Claude; de Brouwer, Arjan P.M.; Van Esch, Hilde; Froyen, Guy; Patsalis, Philippos C.

    2009-01-01

    Recent studies and advances in high-density oligonucleotide arrays have shown that microdeletions and microduplications occur at a high frequency in the human genome, causing various genetic conditions including mental retardation. Thus far little is known about the pathways leading to this disease, and implementation of microarrays is hampered by their increasing cost and complexity, underlining the need for new diagnostic tools. The aim of this study was to introduce a new targeted platform called “chromosome X exon-specific array” and to apply this new platform to screening of 20 families (including one blind positive control) with suspected X-linked mental retardation, to identify new causative X-linked mental retardation genes. The new microarray contains of 21,939 oligonucleotides covering 92.9% of all exons of all genes on chromosome X. Patient screening resulted in successful identification of the blind positive control included in the sample of 20 families, and one of the remaining 19 families was found to carry a 1.78-kilobase deletion involving all exons of pseudogene BRAF2. The BRAF2 deletion segregated in the family and was not found in 200 normal male samples, and no copy number variations are reported in this region. Further studies and focused investigation of X-linked disorders have the potential to reveal the molecular basis of human genetic pathological conditions that are caused by copy-number changes in chromosome X genes. PMID:19779134

  20. A new chromosome x exon-specific microarray platform for screening of patients with X-linked disorders.

    PubMed

    Bashiardes, Stavros; Kousoulidou, Ludmila; van Bokhoven, Hans; Ropers, Hans-Hilger; Chelly, Jamel; Moraine, Claude; de Brouwer, Arjan P M; Van Esch, Hilde; Froyen, Guy; Patsalis, Philippos C

    2009-11-01

    Recent studies and advances in high-density oligonucleotide arrays have shown that microdeletions and microduplications occur at a high frequency in the human genome, causing various genetic conditions including mental retardation. Thus far little is known about the pathways leading to this disease, and implementation of microarrays is hampered by their increasing cost and complexity, underlining the need for new diagnostic tools. The aim of this study was to introduce a new targeted platform called "chromosome X exon-specific array" and to apply this new platform to screening of 20 families (including one blind positive control) with suspected X-linked mental retardation, to identify new causative X-linked mental retardation genes. The new microarray contains of 21,939 oligonucleotides covering 92.9% of all exons of all genes on chromosome X. Patient screening resulted in successful identification of the blind positive control included in the sample of 20 families, and one of the remaining 19 families was found to carry a 1.78-kilobase deletion involving all exons of pseudogene BRAF2. The BRAF2 deletion segregated in the family and was not found in 200 normal male samples, and no copy number variations are reported in this region. Further studies and focused investigation of X-linked disorders have the potential to reveal the molecular basis of human genetic pathological conditions that are caused by copy-number changes in chromosome X genes.

  1. X-linked gene expression in the Virginia opossum: differences between the paternally derived Gpd and Pgk-A loci

    SciTech Connect

    Samollow, P.B.; Ford, A.L.; VandeBerg, J.L.

    1987-01-01

    Expression of X-linked glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate kinase-A (PGK-A) in the Virginia opossum (Didelphis virginiana) was studied electrophoretically in animals from natural populations and those produced through controlled laboratory crosses. Blood from most of the wild animals exhibited a common single-banded phenotype for both enzymes. Rare variant animals, regardless of sex, exhibited single-banded phenotypes different in mobility from the common mobility class of the respective enzyme. The laboratory crosses confirmed the allelic basis for the common and rare phenotypes. Transmission of PGK-A phenotypes followed the pattern of determinate (nonrandom) inactivation of the paternally derived Pgk-A allele, and transmission of G6PD also was consistent with this pattern. A survey of tissue-specific expression of G6PD phenotypes of heterozygous females revealed, in almost all tissues, three-banded patterns skewed in favor of the allele that was expressed in blood cells. Three-banded patterns were never observed in males or in putatively homozygous females. These patterns suggest simultaneous, but unequal, expression of the maternally and paternally derived Gpd alleles within individual cells. The absence of such partial expression was noted in a parallel survey of females heterozygous at the Pgd-A locus. Thus, it appears that Gpd and Pgk-A are X-linked in D. virginiana and subject to preferential paternal allele inactivation, but that dosage compensation may not be complete for all paternally derived X-linked genes.

  2. A New Splicing Mutation in the L1CAM Gene Responsible for X-Linked Hydrocephalus (HSAS).

    PubMed

    Ferese, Rosangela; Zampatti, Stefania; Griguoli, Anna Maria Pia; Fornai, Francesco; Giardina, Emiliano; Barrano, Giuseppe; Albano, Veronica; Campopiano, Rosa; Scala, Simona; Novelli, Giuseppe; Gambardella, Stefano

    2016-07-01

    X-linked hydrocephalus (XLH) is a genetic disorder leading to a syndrome characterized by mental retardation, bilateral adducted thumbs, and spasticity of upper and lower limbs. In most cases, X-linked mutation leads to a defective activity of the neuronal cell adhesion molecule L1CAM (L1 cell adhesion molecule, OMIM 308840). Depending on mutations of L1CAM, four X-linked neurological syndromes have been described. These syndromes are very different albeit each one possesses marked variability. In the present study, we describe a novel L1CAM mutation in a 33-year-old woman reporting two voluntary terminations of pregnancy due to fetal hydrocephalus. The genetic analysis identified the potential splicing variant c.1267+5delG. When analyzed in vitro, this mutation produces the skipping of exon 10. The same mutation was confirmed in analyzing DNA from amniocytes from the second pregnancy, and ultrasound scan and autopsy confirmed the occurrence of a severe L1 syndrome. These data describe a novel L1 mutation which improves our understanding on genotype-phenotype correlation while confirming the importance of prenatal screening for L1CAM mutations. PMID:27207492

  3. Variation in the X-linked EFHC2 gene is associated with social cognitive abilities in males.

    PubMed

    Startin, Carla M; Fiorentini, Chiara; de Haan, Michelle; Skuse, David H

    2015-01-01

    Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males. PMID:26107779

  4. FG syndrome, an X-linked multiple congenital anomaly syndrome: The clinical phenotype and an algorithm for diagnostic testing

    PubMed Central

    Clark, Robin Dawn; Graham, John M.; Friez, Michael J.; Hoo, Joe J.; Jones, Kenneth Lyons; McKeown, Carole; Moeschler, John B.; Raymond, F. Lucy; Rogers, R. Curtis; Schwartz, Charles E.; Battaglia, Agatino; Lyons, Michael J.; Stevenson, Roger E.

    2014-01-01

    FG syndrome is a rare X-linked multiple congenital anomaly-cognitive impairment disorder caused by the p.R961W mutation in the MED12 gene. We identified all known patients with this mutation to delineate their clinical phenotype and devise a clinical algorithm to facilitate molecular diagnosis. We ascertained 23 males with the p.R961W mutation in MED12 from 9 previously reported FG syndrome families and 1 new family. Six patients are reviewed in detail. These 23 patients were compared with 48 MED12 mutation-negative patients, who had the clinical diagnosis of FG syndrome. Traits that best discriminated between these two groups were chosen to develop an algorithm with high sensitivity and specificity for the p.R961W MED12 mutation. FG syndrome has a recognizable dysmorphic phenotype with a high incidence of congenital anomalies. A family history of X-linked mental retardation, deceased male infants, and/or multiple fetal losses was documented in all families. The algorithm identifies the p.R961W MED12 mutation-positive group with 100% sensitivity and 90% spec-ificity. The clinical phenotype of FG syndrome defines a recognizable pattern of X-linked multiple congenital anomalies and cognitive impairment. This algorithm can assist the clinician in selecting the patients for testing who are most likely to have the recurrent p.R961W MED12 mutation. PMID:19938245

  5. Control of canine distemper.

    PubMed

    Chappuis, G

    1995-05-01

    Control of canine distemper can realistically only be achieved by the use of vaccination. The types of vaccine in current use are described, together with some of the problems encountered such as interference by maternal antibodies, and usage in species other than dogs. Modified live viral vaccines, as used for more than thirty years, have proved very effective. Nevertheless there is scope for some improvement in vaccine efficacy and recent developments in genetic recombinant methods are described. PMID:8588329

  6. [Canine histoplasmosis in Japan].

    PubMed

    Sano, Ayako; Miyaji, Makoto

    2003-01-01

    Histoplasmosis is a fungal infection caused by Histoplasma capsulatum and is distributed a worldwide. Although the disease has been treated as an imported mycosis, some autochthonous human, 1 equine and 4 canine cases suggested that the disease is endemic. Histoplasmosis is classified depending on the variety of causative agent. Histoplasmosis farciminosi known as pseudofarcy, is manifested only in Perissodactyla where it invades lymph nodes and lymph ducts, and is recognized by isolation from horses. Historically, Japan was one of the endemic areas of pseudofarcy before World War II, and more than 20,000 cases were recorded in horses used by the military. Interestingly, Japanese canine histoplasmosis uniformly showed skin ulcers and granulomatous lesions on the skin without pulmonary or gastrointestinal involvement, both of which were very similar to pseudofarcy. It was diagnosed as histoplasmosis by the detection of internal transcribed spacer legions of rRNA gene of H. capsulatum from paraffin embedded tissue samples. Furthermore, the fungal isolate from the human case with no history of going abroad or immigrating was identified as H. capsulatum var. farciminosum by a gene sequence. These facts indicated that pseudofarcy is not only an infectious disease in horses, but also a zoonotic fungal infection. Japanese autochthonous canine histoplasmosis might be a heteroecism of pseudofarcy because of its likeness to the human case, the similarity of clinical manifestations and the historical background at this stage.

  7. Duchenne Muscular Dystrophy Gene Therapy in the Canine Model

    PubMed Central

    2015-01-01

    Abstract Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID:25710459

  8. The effect of Lorenzo's oil on oxidative stress in X-linked adrenoleukodystrophy.

    PubMed

    Deon, Marion; Wajner, Moacir; Sirtori, Lisana R; Fitarelli, Douglas; Coelho, Daniella M; Sitta, Angela; Barschak, Alethéa G; Ferreira, Gustavo C; Haeser, Alexsandro; Giugliani, Roberto; Vargas, Carmen R

    2006-09-25

    X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder biochemically characterized by the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C(26:0)) and tetracosanoic acid (C(24:0)), in tissues and biological fluids. Although patients affected by this disorder predominantly present central and peripheral demyelination as well as adrenal insufficiency, the mechanisms underlying the brain damage in X-ALD are poorly known. The current treatment of X-ALD with glyceroltrioleate (C(18:1))/glyceroltrierucate (C(22:1)) (Lorenzo's oil, LO) combined with a VLCFA-poor diet normalizes VLCFA concentrations, but the neurological symptoms persist or even progress in symptomatic patients. Considering that free radical generation is involved in various neurodegenerative disorders and that in a previous study we showed evidence that oxidative stress is probably involved in the pathophysiology of X-ALD symptomatic patients, in the present study we evaluated various oxidative stress parameters, namely thiobarbituric acid reactive species (TBA-RS) and total antioxidant reactivity (TAR) in plasma, as well as the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes from symptomatic and asymptomatic X-ALD patients and verified whether LO treatment and a VLCFA restricted diet could change these parameters. We observed a significant increase of plasma TBA-RS in symptomatic and asymptomatic X-ALD patients, reflecting induction of lipid peroxidation even before the disease was manifested. In addition, LO treatment did not alter this profile. Furthermore, plasma TAR measurement of X-ALD patients was not different from that of controls. Similarly, the antioxidant enzyme activities CAT, SOD and GPx were not altered in erythrocyte from X-ALD patients as compared to controls. We also examined the in vitro effects of hexacosanoic acid (C(26:0)) and tetracosanoic acid (C(24

  9. An ex vivo gene therapy approach in X-linked retinoschisis

    PubMed Central

    Bashar, Abu E.; Metcalfe, Andrew L.; Viringipurampeer, Ishaq A.; Yanai, Anat; Gregory-Evans, Cheryl Y.

    2016-01-01

    Purpose X-linked retinoschisis (XLRS) is juvenile-onset macular degeneration caused by haploinsufficiency of the extracellular cell adhesion protein retinoschisin (RS1). RS1 mutations can lead to either a non-functional protein or the absence of protein secretion, and it has been established that extracellular deficiency of RS1 is the underlying cause of the phenotype. Therefore, we hypothesized that an ex vivo gene therapy strategy could be used to deliver sufficient extracellular RS1 to reverse the phenotype seen in XLRS. Here, we used adipose-derived, syngeneic mesenchymal stem cells (MSCs) that were genetically modified to secrete human RS1 and then delivered these cells by intravitreal injection to the retina of the Rs1h knockout mouse model of XLRS. Methods MSCs were electroporated with two transgene expression systems (cytomegalovirus (CMV)-controlled constitutive and doxycycline-induced Tet-On controlled inducible), both driving expression of human RS1 cDNA. The stably transfected cells, using either constitutive mesenchymal stem cell (MSC) or inducible MSC cassettes, were assayed for their RS1 secretion profile. For single injection studies, 100,000 genetically modified MSCs were injected into the vitreous cavity of the Rs1h knockout mouse eye at P21, and data were recorded at 2, 4, and 8 weeks post-injection. The control groups received either unmodified MSCs or vehicle injection. For the multiple injection studies, the mice received intravitreal MSC injections at P21, P60, and P90 with data collection at P120. For the single- and multiple-injection studies, the outcomes were measured with electroretinography, optokinetic tracking responses (OKT), histology, and immunohistochemistry. Results Two lines of genetically modified MSCs were established and found to secrete RS1 at a rate of 8 ng/million cells/day. Following intravitreal injection, RS1-expressing MSCs were found mainly in the inner retinal layers. Two weeks after a single injection of MSCs, the

  10. A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map.

    PubMed Central

    Schanen, N C; Dahle, E J; Capozzoli, F; Holm, V A; Zoghbi, H Y; Francke, U

    1997-01-01

    Although familial recurrences of Rett syndrome (RTT) comprise only approximately 1% of the reported cases, it is these cases that hold the key for the understanding of the genetic basis of the disorder. Families in which RTT occurs in mother and daughter, aunt and niece, and half sisters are consistent with dominant inheritance and variable expressivity of the phenotype. Recurrence of RTT in sisters is likely due to germ-line mosaicism in one of the parents, rather than to recessive inheritance. The exclusive occurrence of classic RTT in females led to the hypothesis that it is X-linked and may be lethal in males. In an X-linked dominant disorder, unaffected obligate-carrier females would be expected to show nonrandom or skewed inactivation of the X chromosome bearing the mutant allele. We investigated the X chromosome inactivation (XCI) patterns in the female members of a newly identified family with recurrence of RTT in a maternal aunt and a niece. Skewing of XCI is present in the obligate carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the XCI pattern in the mother of affected half sisters shows random XCI, suggesting germ-line mosaicism as the cause of repeated transmission in this family. To determine which regions of the X chromosome were inherited concordantly/discordantly by the probands, we genotyped the individuals in the aunt-niece family and two previously reported pairs of half sisters. These combined exclusion-mapping data allow us to exclude the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. This represents an extension of the previous exclusion map. Images Figure 1 Figure 2 PMID:9326329

  11. siRNAs from an X-linked satellite repeat promote X-chromosome recognition in Drosophila melanogaster.

    PubMed

    Menon, Debashish U; Coarfa, Cristian; Xiao, Weimin; Gunaratne, Preethi H; Meller, Victoria H

    2014-11-18

    Highly differentiated sex chromosomes create a lethal imbalance in gene expression in one sex. To accommodate hemizygosity of the X chromosome in male fruit flies, expression of X-linked genes increases twofold. This is achieved by the male- specific lethal (MSL) complex, which modifies chromatin to increase expression. Mutations that disrupt the X localization of this complex decrease the expression of X-linked genes and reduce male survival. The mechanism that restricts the MSL complex to X chromatin is not understood. We recently reported that the siRNA pathway contributes to localization of the MSL complex, raising questions about the source of the siRNAs involved. The X-linked 1.688 g/cm(3) satellite related repeats (1.688(X) repeats) are restricted to the X chromosome and produce small RNA, making them an attractive candidate. We tested RNA from these repeats for a role in dosage compensation and found that ectopic expression of single-stranded RNAs from 1.688(X) repeats enhanced the male lethality of mutants with defective X recognition. In contrast, expression of double-stranded hairpin RNA from a 1.688(X) repeat generated abundant siRNA and dramatically increased male survival. Consistent with improved survival, X localization of the MSL complex was largely restored in these males. The striking distribution of 1.688(X) repeats, which are nearly exclusive to the X chromosome, suggests that these are cis-acting elements contributing to identification of X chromatin. PMID:25368194

  12. Absence of canine papillomavirus sequences in canine mammary tumours.

    PubMed

    Sardon, D; Blundell, R; Burrai, G P; Alberti, A; Tore, G; Passino, E Sanna; Antuofermo, E

    2015-01-01

    Human papillomaviruses (PVs) are found in human breast cancer tissue; however, it remains controversial as to whether these viruses play a role in the aetiology of this tumour. There has been minimal study of whether PVs are found in normal or abnormal mammary glands of animals. The present study investigated whether a PV sequence could be found in the mammary glands of 33 female dogs by rolling circle amplification and polymerase chain reaction. No PV DNA was found in normal or neoplastic canine mammary tissues, suggesting that canine PVs are probably not involved in the pathogenesis of canine mammary neoplasia. PMID:25435511

  13. Compensatory embryonic response to allele-specific inactivation of the murine X-linked gene Hcfc1.

    PubMed

    Minocha, Shilpi; Sung, Tzu-Ling; Villeneuve, Dominic; Lammers, Fabienne; Herr, Winship

    2016-04-01

    Early in female mammalian embryonic development, cells randomly inactivate one of the two X chromosomes to achieve overall equal inactivation of parental X-linked alleles. Hcfc1 is a highly conserved X-linked mouse gene that encodes HCF-1 - a transcriptional co-regulator implicated in cell proliferation in tissue culture cells. By generating a Cre-recombinase inducible Hcfc1 knock-out (Hcfc1(lox)) allele in mice, we have probed the role of HCF-1 in actively proliferating embryonic cells and in cell-cycle re-entry of resting differentiated adult cells using a liver regeneration model. HCF-1 function is required for both extraembryonic and embryonic development. In heterozygous Hcfc1(lox/+) female embryos, however, embryonic epiblast-specific Cre-induced Hcfc1 deletion (creating an Hcfc1(epiKO) allele) around E5.5 is well tolerated; it leads to a mixture of HCF-1-positive and -negative epiblast cells owing to random X-chromosome inactivation of the wild-type or Hcfc1(epiKO) mutant allele. At E6.5 and E7.5, both HCF-1-positive and -negative epiblast cells proliferate, but gradually by E8.5, HCF-1-negative cells disappear owing to cell-cycle exit and apoptosis. Although generating a temporary developmental retardation, the loss of HCF-1-negative cells is tolerated, leading to viable heterozygous offspring with 100% skewed inactivation of the X-linked Hcfc1(epiKO) allele. In resting adult liver cells, the requirement for HCF-1 in cell proliferation was more evident as hepatocytes lacking HCF-1 fail to re-enter the cell cycle and thus to proliferate during liver regeneration. The survival of the heterozygous Hcfc1(epiKO/+) female embryos, even with half the cells genetically compromised, illustrates the developmental plasticity of the post-implantation mouse embryo - in this instance, permitting survival of females heterozygous for an X-linked embryonic lethal allele.

  14. MRI demyelination pattern and clinical course in a child with cerebral X-linked adrenoleukodystrophy (X-ALD)

    PubMed Central

    Löbel, Ulrike; Wölfl, Matthias; Schlegel, Paul-Gerhardt; Warmuth-Metz, Monika

    2015-01-01

    The clinical spectrum in boys with X-linked adrenoleukodystrophy (X-ALD) ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. In the individual case, the disease course still remains unpredictable. Research findings suggest an important role of brain magnetic resonance imaging (MRI) lesion patterns as prognostic markers for X-ALD. Hence, familiarity with imaging features of childhood X-ALD in combination with clinical manifestation is required in order to stratify affected patients for therapy. We report on MRI findings and clinical course of cerebral X-ALD in a young boy with a rare subtype of white matter demyelination. PMID:25848550

  15. MRI demyelination pattern and clinical course in a child with cerebral X-linked adrenoleukodystrophy (X-ALD).

    PubMed

    Nowak, Johannes; Löbel, Ulrike; Wölfl, Matthias; Schlegel, Paul-Gerhardt; Warmuth-Metz, Monika

    2015-04-01

    The clinical spectrum in boys with X-linked adrenoleukodystrophy (X-ALD) ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. In the individual case, the disease course still remains unpredictable. Research findings suggest an important role of brain magnetic resonance imaging (MRI) lesion patterns as prognostic markers for X-ALD. Hence, familiarity with imaging features of childhood X-ALD in combination with clinical manifestation is required in order to stratify affected patients for therapy. We report on MRI findings and clinical course of cerebral X-ALD in a young boy with a rare subtype of white matter demyelination.

  16. Situs inversus totalis and a novel ZIC3 mutation in a family with X-linked heterotaxy.

    PubMed

    D'Alessandro, Lisa C A; Casey, Brett; Siu, Victoria Mok

    2013-01-01

    Disorders of laterality consist of a complex set of malformations resulting from failure to establish normal asymmetry along the left-right axis, and include both heterotaxy and situs inversus totalis. Zinc fingers in cerebellum 3 (ZIC3) was the first gene to be definitively associated with heterotaxy syndromes in humans (OMIM #306955), with 13 mutations previously described in both familial and sporadic cases. We now report the clinical and molecular characterization of a five-generation family originally reported in 1974 as having X-linked dextrocardia. Longitudinal follow-up revealed that this family has X-linked heterotaxy due to a missense mutation, c.1048A>G(R350G), in the third zinc finger domain of ZIC3. The pedigree demonstrates the first reported case of situs inversus totalis associated with a ZIC3 mutation in a male and the second reported case of incomplete penetrance in an unaffected transmitting male, as well as a wide range of phenotypes of varying severity. Several affected members also exhibit renal and hindgut malformations, consistent with previously reported secondary features in ZIC3 mutations. The spectrum of features in this family emphasizes the importance of thorough molecular and imaging studies in both sporadic and familial cases of heterotaxy to ensure accurate prenatal diagnosis and recurrence risk counseling.

  17. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

    PubMed Central

    Reinstein, Eyal; Frentz, Sophia; Morgan, Tim; García-Miñaúr, Sixto; Leventer, Richard J; McGillivray, George; Pariani, Mitchel; van der Steen, Anthony; Pope, Michael; Holder-Espinasse, Muriel; Scott, Richard; Thompson, Elizabeth M; Robertson, Terry; Coppin, Brian; Siegel, Robert; Bret Zurita, Montserrat; Rodríguez, Jose I; Morales, Carmen; Rodrigues, Yuri; Arcas, Joaquín; Saggar, Anand; Horton, Margaret; Zackai, Elaine; Graham, John M; Rimoin, David L; Robertson, Stephen P

    2013-01-01

    Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance. PMID:23032111

  18. Screening of 20 patients with X-linked mental retardation using chromosome X-specific array-MAPH.

    PubMed

    Kousoulidou, Ludmila; Parkel, Sven; Zilina, Olga; Palta, Priit; Puusepp, Helen; Remm, Maido; Turner, Gillian; Boyle, Jackie; van Bokhoven, Hans; de Brouwer, Arjan; Van Esch, Hilde; Froyen, Guy; Ropers, Hans-Hilger; Chelly, Jamel; Moraine, Claude; Gecz, Jozef; Kurg, Ants; Patsalis, Philippos C

    2007-01-01

    The rapid advancement of high-resolution DNA copy number assessment methods revealed the significant contribution of submicroscopic genetic imbalances to abnormal phenotypes, including mental retardation. In order to detect submicroscopic genetic imbalances, we have screened 20 families with X-linked mental retardation (XLMR) using a chromosome X-specific array-MAPH platform with median resolution of 238kb. Among the 20 families, 18 were experimental, as they were not previously screened with any microarray method, and two were blind controls with known aberrations, as they were previously screened by array-CGH. This study presents the first clinical application of chromosome X-specific array-MAPH methodology. The screening of 20 affected males from 20 unrelated XLMR families resulted in the detection of an unknown deletion, spanning a region of 7-23kb. Family studies and population screening demonstrated that the detected deletion is an unknown rare copy number variant. One of the control samples, carrying approximately 6-Mb duplication was correctly identified, moreover it was found to be interrupted by a previously unknown 19kb region of normal copy number. The second control 50kb deletion was not identified, as this particular region was not covered by array-MAPH probes. This study demonstrates that the chromosome X-specific array-MAPH platform is a valuable tool for screening patients with XLMR, or other X-linked disorders, and emerges the need for introducing new high-resolution screening methods for the detection of genetic imbalances.

  19. Two mutational hotspots in the interleukin-2 receptor {gamma} chain gene causing human X-linked severe combined immunodeficiency

    SciTech Connect

    Pepper, A.E.; Puck, J.M.; Buckley, R.H.

    1995-09-01

    Human severe combined immunodeficiency (SCID), a syndrome of profoundly impaired cellular and humoral immunity, is most commonly caused by mutations in the X-linked gene for interleukin-2 (IL-2) receptor {gamma} chain (IL2RG). For mutational analysis of IL2RG in males with SCID, SSCP screening was followed by DNA sequencing. Of 40 IL2RG mutations found in unrelated SCID patients, 6 were point mutations at the CpG dinucleotide at cDNA 690-691, encoding amino acid R226. This residue lies in the extracellular domain of the protein in a region not previously recognized to be significantly conserved in the cytokine receptor gene family, 11 amino acids upstream from the highly conserved WSXWS motif. Three additional instances of mutation at another CpG dinucleotide at cDNA 879 produced a premature termination signal in the intracellular domain of IL2RG, resulting in loss of the SH2-homologous intracellular domain known to be essential for signaling from the IL-2 receptor complex. Mutations at these two hotspots constitute >20% of the X-linked SCID mutations found by our group and a similar proportion of all reported IL2RG mutations. 41 refs., 5 figs., 1 tab.

  20. Photoreceptor Rescue by an Abbreviated Human RPGR Gene in a Murine Model of X-linked Retinitis Pigmentosa

    PubMed Central

    Pawlyk, Basil S.; Adamian, Michael; Sun, Xun; Bulgakov, Oleg V.; Shu, Xinhua; Smith, Alexander J.; Berson, Eliot L.; Ali, Robin R.; Khani, Shahrokh; F.Wright, Alan; Sandberg, Michael A.; Li, Tiansen

    2015-01-01

    The X-linked RP3 gene codes for the ciliary protein RPGR and accounts for over 10% of inherited retinal degenerations. The critical RPGR-ORF15 splice variant contains a highly repetitive purine-rich linker region that renders it unstable and difficult to adapt for gene therapy. To test the hypothesis that the precise length of the linker region is not critical for function, we evaluated whether AAV-mediated replacement gene therapy with a human ORF15 variant containing in-frame shortening of the linker region could reconstitute RPGR function in vivo. We delivered human RPGR-ORF15 replacement genes with deletion of most (314-codons, “short form”) or 1/3 (126-codons, “long form”) of the linker region to Rpgr null mice. Human RPGR-ORF15 expression was detected post-treatment with both forms of ORF15 transgenes. However, only the long form correctly localized to the connecting cilia and led to significant functional and morphological rescue of rods and cones. Thus the highly repetitive region of RPGR is functionally important but that moderate shortening of its length, which confers the advantage of added stability, preserves its function. These findings provide a theoretical basis for optimizing replacement gene design in clinical trials for X-linked RP3. PMID:26348595

  1. X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15.

    PubMed

    Demirci, F Yesim K; Rigatti, Brian W; Wen, Gaiping; Radak, Amy L; Mah, Tammy S; Baic, Corrine L; Traboulsi, Elias I; Alitalo, Tiina; Ramser, Juliane; Gorin, Michael B

    2002-04-01

    X-linked cone-rod dystrophy (COD1) is a retinal disease that primarily affects the cone photoreceptors; the disease was originally mapped to a limited region of Xp11.4. We evaluated the three families from our original study with new markers and clinically reassessed all key recombinants; we determined that the critical intervals in families 2 and 3 overlapped the RP3 locus and that a status change (from affected to probably unaffected) of a key recombinant individual in family 1 also reassigned the disease locus to include RP3 as well. Mutation analysis of the entire RPGR coding region identified two different 2-nucleotide (nt) deletions in ORF15, in family 2 (delAG) and in families 1 and 3 (delGG), both of which result in a frameshift leading to altered amino acid structure and early termination. In addition, an independent individual with X-linked cone-rod dystrophy demonstrated a 1-nt insertion (insA) in ORF15. The presence of three distinct mutations associated with the same disease phenotype provides strong evidence that mutations in RPGR exon ORF15 are responsible for COD1. Genetic heterogeneity was observed in three other families, including the identification of an in-frame 12-nt deletion polymorphism in ORF15 that did not segregate with the disease in one of these families.

  2. Terminal osseous dysplasia and pigmentary defects: clinical characterization of a novel male lethal X-linked syndrome.

    PubMed

    Bacino, C A; Stockton, D W; Sierra, R A; Heilstedt, H A; Lewandowski, R; Van den Veyver, I B

    2000-09-11

    We describe a new syndrome of distal limb anomalies and pigmentary skin defects in 10 females of a large, four-generation pedigree. The family was ascertained through a 4-month-old infant girl with multiple anomalies, including hypertelorism, iris colobomas, low-set ears, midface hypoplasia, punched-out pigmentary abnormalities over the face and scalp, generalized brachydactyly, and digital fibromatosis. No affected males were identified in this pedigree. Affected females had a lower than normal male-to-female ratio of liveborn offspring, and some of them also had a history of several miscarriages. These findings, together with a significant variability in the phenotype of the affected females, suggest that this condition is inherited in an X-linked dominant fashion, with prenatal male lethality, and that X-inactivation plays an important role in the phenotypic expression of the disease. The syndrome has been described twice in the literature, but only in sporadic cases; it was therefore not recognized as a mendelian entity. Because the most consistent findings are anomalies of the distal skeleton of the limbs and localized pigmentary abnormalities of the skin, we named the syndrome "terminal osseous dysplasia with pigmentary defects." This condition, though rare, can be added to the small group of male lethal X-linked dominant disorders in humans.

  3. A novel splicing site mutation of the GPR143 gene in a Chinese X-linked ocular albinism pedigree.

    PubMed

    Cai, C Y; Zhu, H; Shi, W; Su, L; Shi, O; Cai, C Q; Ling, C; Li, W D

    2013-01-01

    Ocular albinism is an X-linked inherited disease characterized by hypopigmentation of the iris and nystagmus. To identify a new disease-causing mutation of ocular albinism, we collected a Han Chinese pedigree with 7 male congenital nystagmus patients over 3 generations. Slit-lamp photography and optical coherence tomography were performed for the proband. Genomic DNA was extracted from a whole blood sample from the proband using the high-salt method. Polymerase chain reaction (PCR) sequencing was carried out for GPR143 and FRMD7 genes. The three-dimensional structures of the wild-type and mutant GPR143 proteins were determined using SWISS-MODEL. The transmission of the disease in the pedigree clearly followed an X-linked pattern. The proband had significant iris and fundus hypopigmentation. Optical coherence tomography showed severe foveal hypoplasias in both eyes of the proband. A novel splicing site (G/C) mutation was found on the boundary of the 6th intron and the 7th exon of the GPR143 gene, resulting in a 9-amino-acid deletion (codons 257-265) in the 6th transmembrane domain of the GPR143 protein. In conclusion, a novel splicing site mutation of the GPR143 gene was found in a Han Chinese congenital ocular albinism pedigree. PMID:24301936

  4. Canine hypoadrenocorticism: Part I

    PubMed Central

    Klein, Susan C.; Peterson, Mark E.

    2010-01-01

    Hypoadrenocorticism (Addison’s disease) has been referred to as “the great pretender,” due to its ability to mimic other common diseases in the dog and thereby represent a diagnostic challenge. Naturally occurring hypoadrenocorticism is an uncommon canine disease. Young, female dogs are overrepresented. Hypoadrenocorticism typically results from immune-mediated destruction of all adrenocortical layers, resulting in deficiencies of min-eralocorticoids (aldosterone) and glucocorticoids (cortisol). A small number of dogs suffer from glucocorticoid deficiency only. Dogs suffering from hypoadrenocorticism may present in a variety of conditions, from a mildly ill dog to a shocky and recumbent dog. This review discusses etiology, pathophysiology, history, physical examination findings, and diagnostic findings in the Addisonian patient. A follow-up article (Part II) will discuss the definitive diagnosis and management strategies for these patients. PMID:20357943

  5. X-linked FHL1 as a novel therapeutic target for head and neck squamous cell carcinoma

    PubMed Central

    Xia, Ronghui; Lin, Lu; Wang, Xu; Xiao, Meng; Zhang, Chenping; Li, Jiang; Ji, Tong; Chen, Wantao

    2016-01-01

    To identify X-linked novel tumor suppressors could provide novel insights to improve prognostic prediction and therapeutic strategy for some cancers. Using bioinformatics and Venn analysis of gene transcriptional profiling, we identified downregulation of X-linked four-and-a-half LIM domains protein 1 (FHL1) gene in head and neck squamous cell carcinoma (HNSCC). FHL1 functions were investigated and confirmed in vitro and in vivo. FHL1 downregulated mechanisms were analyzed in HNSCCs by using methylation specific PCR, bisulfate-based sequencing, 5-Aza-dC treatment and chromatin immunoprecipitation assays. Two independent HNSCC cohorts (the training cohort n = 105 and the validation cohort n = 101) were enrolled to evaluate clinical implications of FHL1 expression by using real-time PCR or immunohistochemistry. FHL1 mRNA and protein expressions were frequently decreased in HNSCCs. FHL1 overexpression or depletion gave rise to suppress or promote cell growth through Cyclin D1, Cyclin E and p27 dysregulations. Abundant occupy of EZH2 or H3K27Me3 was observed in FHL1 promoter except for DNA hypermethylation. Reduced FHL1 mRNA expression was notably associated with poor differentiation (p = 0.020). Multivariate analysis demonstrated FHL1 mRNA expression was identified as independent prognostic predictors of overall survival (OS) (p = 0.036; HR 0.520; Cl, 0.283–0.958) and disease-free survival (DFS) (p = 0.041; HR 0.527; Cl, 0.284–0.975), which was validated by another independent cohort (p = 0.021; HR 0.404; Cl, 0.187–0.871 for OS; p = 0.011; HR 0.407; Cl, 0.203–0.815 for DFS). These results suggest epigenetic silencing of X-linked FHL1 may have an important role in adjuvant therapeutic intervention of HNSCCs and is an independent prognostic factor in patients with HNSCCs. PMID:26908444

  6. X-linked borderline mental retardation with prominent behavioral disturbance: Phenotype, genetic localization, and evidence for disturbed monoamine metabolism

    SciTech Connect

    Brunner, H.G.; Nelen, M.R.; Zandvoort, P. van; Abeling, N.G.G.M.; Gennip, A.H. van; Ropers, H.H.; Oost, B.A. van ); Wolters, E.C.; Kuiper, M.A. )

    1993-06-01

    The authors have identified a large Dutch kindred with a new form of X-linked nondysmorphic mild mental retardation. All affected males in this family show very characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior include arson, attempted rape, and exhibitionism. Attempted suicide has been reported in a single case. The locus for this disorder could be assigned to the Xp11-21 interval between DXS7 and DXS77 by linkage analysis using markers spanning the X chromosome. A maximal multipoint lod score of 3.69 was obtained at the monoamine oxidase type A (MAOA) monoamine metabolism. These data are compatible with a primary defect in the structural gene for MAOA and/or monoamine oxidase type B (MAOB). Normal platelet MAOB activity suggests that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency. 34 refs., 4 figs., 4 tabs.

  7. X-linked inhibitor of apoptosis protein functions as a cofactor in transforming growth factor-beta signaling.

    PubMed

    Birkey Reffey, S; Wurthner, J U; Parks, W T; Roberts, A B; Duckett, C S

    2001-07-13

    X-linked inhibitor of apoptosis protein (XIAP) is a potent suppressor of apoptotic cell death, which functions by directly inhibiting caspases, the principal effectors of apoptosis. Here we report that XIAP can also function as a cofactor in the regulation of gene expression by transforming growth factor-beta (TGF-beta). XIAP, but not the related proteins c-IAP1 or c-IAP2, associated with several members of the type I class of the TGF-beta receptor superfamily and potentiated TGF-beta-induced signaling. Although XIAP-mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B was found to require the TGF-beta signaling intermediate Smad4, the ability of XIAP to suppress apoptosis was found to be Smad4-independent. These data implicate a role for XIAP in TGF-beta-mediated signaling that is distinct from its anti-apoptotic functions.

  8. The first de novo mutation of the connexin 32 gene associated with X linked Charcot-Marie-Tooth disease.

    PubMed

    Meggouh, F; Benomar, A; Rouger, H; Tardieu, S; Birouk, N; Tassin, J; Barhoumi, C; Yahyaoui, M; Chkili, T; Brice, A; LeGuern, E

    1998-03-01

    X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary motor and sensory neuropathy caused by mutations in the connexin 32 gene (Cx32). Using the SSCP technique and direct sequencing of PCR amplified genomic DNA fragments of the Cx32 gene from a Moroccan patient and her relatives, we identified the first de novo mutation of the Cx32 gene, consisting of a deletion of a G residue at position 499 in the Cx32 open reading frame. This previously unreported mutation produces a frameshift at position 147 in the protein and introduces a premature stop codon (TAG) at nucleotide 643, which results in the production of a truncated Cx32 molecule. This mutation illustrates the risk of an erroneous diagnosis of autosomal recessive CMT, especially in populations where consanguineous unions are frequent, and its consequences for genetic counselling, which can be avoided by molecular analysis.

  9. Gastric adenocarcinoma in the context of X-linked agammaglobulinemia: case report and review of the literature.

    PubMed

    Staines Boone, Aidé Tamara; Torres Martínez, María Guadalupe; López Herrera, Gabriela; de Leija Portilla, Julia O; Espinosa Padilla, Sara Elva; Espinosa Rosales, Francisco J; Lugo Reyes, Saúl Oswaldo

    2014-02-01

    The hallmarks of X-linked Agammaglobulinemia (XLA) are panhypogammaglobulinemia, absent B-cells, and recurrent sinopulmonary and gastrointestinal infections starting at an early age, as well as other infections like cellulitis, meningitis, arthritis and sepsis. A number of non-infectious complications have been reported in these patients, including autoimmune diseases and malignancy, especially lymphomas. Here, we report the case of a 30-year old man who developed gastric adenocarcinoma in the context of XLA. Previous reports of, and hypotheses addressing the development of cancer in patients with XLA, are also summarized. Solid cancer in XLA affects mainly the gastrointestinal tract and seems to be related to chronic infection. A natural evolution can be traced back from gastric adenocarcinoma to megaloblastic anemia due to achlorhydria in the context of chronic infection; periodic endoscopy thus seems justified to detect and treat carcinoma in early stages. PMID:24338562

  10. Relapsing Remitting Multiple Sclerosis in X-Linked Charcot-Marie-Tooth Disease with Central Nervous System Involvement

    PubMed Central

    Karadima, Georgia; Floroskoufi, Paraskewi; Raftopoulou, Maria; Panas, Marios

    2015-01-01

    We report a patient with relapsing remitting multiple sclerosis (MS) and X-linked Charcot-Marie-Tooth disease (CMTX), carrying a GJB1 mutation affecting connexin-32 (c.191G>A, p. Cys64Tyr) which was recently reported by our group. This is the third case report of a patient with CMTX developing MS, but it is unique in the fact that other family members carrying the same mutation were found to have asymptomatic central nervous system (CNS) involvement (diffuse white matter hyperintensity on brain MRI and extensor plantars). Although this may be a chance association, the increasing number of cases with CMTX and MS, especially with mutations involving the CNS, may imply some causative effect and provide insights into MS pathogenesis. PMID:25883816

  11. Bilateral periventricular heterotopias in an X-linked dominant transmission in a family with two affected males.

    PubMed

    Gérard-Blanluet, Marion; Sheen, Volney; Machinis, Kalotina; Neal, Jason; Apse, Kira; Danan, Claude; Sinico, Martine; Brugières, Pierre; Mage, Katia; Ratsimbazafy, Lanto; Elbez, Annie; Janaud, Jean-Claude; Amselem, Serge; Walsh, Christopher; Encha-Razavi, Férechté

    2006-05-15

    We report on the case of dizygotic twin boys, born prematurely to an asymptomatic mother. Bilateral periventricular heterotopias with enlarged ventricles were discovered at birth in both twins. One of the twins died prematurely of bronchopulmonary complications, and was shown to have several neuropathological anomalies (microgyria, thin corpus callosum, and reduced white matter). The surviving twin had mental retardation, without epilepsy. MRI of the mother showed asymptomatic periventricular heterotopias without ventricular enlargement. She had two affected daughters also with asymptomatic periventricular heterotopias. A point mutation in the last coding exon 48 of the Filamin A (FLNA) gene (7922c > t) was discovered on sequencing and segregated with the affected individuals. This family has a classical X-linked dominant BPNH pathology, with greater severity in males than females. The location of the FLNA mutation is discussed in light of the neuropathological anomalies and mental retardation in male patients.

  12. A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A.

    PubMed

    Lederer, Damien; Shears, Debbie; Benoit, Valérie; Verellen-Dumoulin, Christine; Maystadt, Isabelle

    2014-05-01

    Kabuki syndrome is a rare malformation syndrome characterized by a typical facial appearance, skeletal anomalies, cardiac malformation, and mild to moderate intellectual disability. In 55-80% of patients with Kabuki syndrome, a mutation in MLL2 is identified. Recently, eight patients with Kabuki syndrome and a mutation in KDM6A were described. In this report, we describe two brothers with a mutation in KDM6A inherited from their mother and maternal grandmother. The two boys have Kabuki-like phenotypes whereas the mother and grandmother present with attenuated phenotypes. This family represents the first instance of hereditary X-linked Kabuki syndrome. We present a short literature review of the patients described with a mutation in KDM6A.

  13. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management

    PubMed Central

    2012-01-01

    X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids (VLCFA; ≥C22). A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60 years. In individual patients the disease course remains unpredictable. This review focuses on the diagnosis and management of patients with X-ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder. PMID:22889154

  14. X-Linked juvenile retinoschisis associated with a 4-base pair insertion at codon 55 of the XLRS1 gene.

    PubMed

    Hiraoka, M; Trese, M T; Shastry, B S

    2000-02-16

    X-linked juvenile retinoschisis (RS) is a bilateral vitreoretinal disorder with no known cure. The gene responsible for the disease was recently isolated by positional cloning methods and a spectrum of mutations has been described in families with RS pathology. In this report, we screened six sporadic cases of RS for mutations in the RS gene to understand the etiology of isolated cases. Our extensive studies revealed a novel 4 bp insertion in one family and the remaining families did not show mutations in the RS gene. This mutation altered the reading frame including codon 55 resulting in nine aberrant amino acid residues. The unaffected mother did not contain this mutation. Additionally, it was not found in 60 normal control chromosomes, suggesting that the insertion mutation is disease related in the family analyzed. PMID:10679210

  15. Generation of functional neutrophils from a mouse model of X-linked chronic granulomatous disorder using induced pluripotent stem cells.

    PubMed

    Mukherjee, Sayandip; Santilli, Giorgia; Blundell, Michael P; Navarro, Susana; Bueren, Juan A; Thrasher, Adrian J

    2011-01-01

    Murine models of human genetic disorders provide a valuable tool for investigating the scope for application of induced pluripotent stem cells (iPSC). Here we present a proof-of-concept study to demonstrate generation of iPSC from a mouse model of X-linked chronic granulomatous disease (X-CGD), and their successful differentiation into haematopoietic progenitors of the myeloid lineage. We further demonstrate that additive gene transfer using lentiviral vectors encoding gp91(phox) is capable of restoring NADPH-oxidase activity in mature neutrophils derived from X-CGD iPSC. In the longer term, correction of iPSC from human patients with CGD has therapeutic potential not only through generation of transplantable haematopoietic stem cells, but also through production of large numbers of autologous functional neutrophils.

  16. Genetic analysis of a 12-year-old boy with X-linked ichthyosis in association with sclerosing glomerulonephritis.

    PubMed

    Song, Yijin; Chen, Jing; Yi, Zhuwen; Dang, Xiqiang; Cheng, Dehua; Wu, Xiaochuan; Tan, Yueqiu

    2013-10-01

    In this study, we report the case of a 12-year-old male with X-linked ichthyosis (XLI) in association with glomerular sclerosis, and our investigation into the deletion pattern of the STS gene and the flanking regions in DNA samples of family members. We observed no features typical of renal osteodystrophy or rickets, with the exception of short stature, in the three afffected male family members. Audiometry, visual acuity and olfactory sensation were normal. By performing PCR analysis of the steroid sulfatase (STS) gene and flanking regions on our patients, we discovered a complete deletion that involved the entire region from DXS1139 to DXF22S1. Further studies are required to determine whether the STS gene or the co-deleted flanking sequences are the cause of renal disease associated with XLI. PMID:23939749

  17. X-linked glucose-6-phosphate dehydrogenase (G6PD) and autosomal 6-phosphogluconate dehydrogenase (6PGD) polymorphisms in baboons

    SciTech Connect

    VandeBerg, J.L.; Aivaliotis, M.J.; Samollow, P.B. )

    1992-12-01

    Electrophoretic polymorphisms of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) were examined in captive colonies of five subspecies of baboons (Papio hamadryas). Phenotype frequencies and family data verified the X-linked inheritance of the G6PD polymorphism. Insufficient family data were available to confirm autosomal inheritance of the 6PGD polymorphism, but the electrophoretic patterns of variant types (putative heterozygotes) suggested the codominant expression of alleles at an autosomal locus. Implications of the G6PD polymorphism are discussed with regard to its utility as a marker system for research on X-chromosome inactivation during baboon development and for studies of clonal cell proliferation and/or cell selection during the development of atherosclerotic lesions in the baboon model. 61 refs., 1 fig., 4 tabs.

  18. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management.

    PubMed

    Engelen, Marc; Kemp, Stephan; de Visser, Marianne; van Geel, Björn M; Wanders, Ronald J A; Aubourg, Patrick; Poll-The, Bwee Tien

    2012-08-13

    X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids (VLCFA; ≥ C22). A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60 years. In individual patients the disease course remains unpredictable. This review focuses on the diagnosis and management of patients with X-ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder.

  19. X-linked retinitis pigmentosa: Report of a large kindred with loss of central vision and preserved peripheral function

    SciTech Connect

    Shastry, B.S.; Trese, M.T.

    1995-11-20

    X-linked retinitis pigmentosa (XLRP) is the most severe form of the inherited forms of retinitis pigmentosa and is clinically variable and genetically heterogeneous. It affects one in 20,000 live births. The affected individuals manifest degeneration of the peripheral retina during the first two decades of life on the basis of night blindness. Central vision usually is preserved until age 50, when the disease advances, affecting central vision and ultimately leading to complete loss of sight. Linkage analysis has shown two loci with a possibility of a third locus on the human X chromosome. The genetic abnormality that causes XLRP is not known at present. Here we describe a large kindred which manifests central loss of field with the preservation of peripheral vision. 5 refs., 1 fig.

  20. X-Linked juvenile retinoschisis associated with a 4-base pair insertion at codon 55 of the XLRS1 gene.

    PubMed

    Hiraoka, M; Trese, M T; Shastry, B S

    2000-02-16

    X-linked juvenile retinoschisis (RS) is a bilateral vitreoretinal disorder with no known cure. The gene responsible for the disease was recently isolated by positional cloning methods and a spectrum of mutations has been described in families with RS pathology. In this report, we screened six sporadic cases of RS for mutations in the RS gene to understand the etiology of isolated cases. Our extensive studies revealed a novel 4 bp insertion in one family and the remaining families did not show mutations in the RS gene. This mutation altered the reading frame including codon 55 resulting in nine aberrant amino acid residues. The unaffected mother did not contain this mutation. Additionally, it was not found in 60 normal control chromosomes, suggesting that the insertion mutation is disease related in the family analyzed.

  1. X-linked creatine transporter defect: a report on two unrelated boys with a severe clinical phenotype.

    PubMed

    Anselm, I A; Anselm, I M; Alkuraya, F S; Salomons, G S; Jakobs, C; Fulton, A B; Mazumdar, M; Rivkin, M; Frye, R; Poussaint, T Young; Marsden, D

    2006-02-01

    We report two unrelated boys with the X-linked creatine transporter defect (CRTR) and clinical features more severe than those previously described with this disorder. These two boys presented at ages 12 and 30 months with severe mental retardation, absent speech development, hypotonia, myopathy and extra-pyramidal movement disorder. One boy has seizures and some dysmorphic features; he also has evidence of an oxidative phosphorylation defect. They both had classical absence of creatine peak on brain magnetic resonance spectroscopy (MRS). In one, however, this critical finding was overlooked in the initial interpretation and was discovered upon subsequent review of the MRS. Molecular studies showed large genomic deletions of a large part of the 3' end of the complete open reading frame of the SLC6A8 gene. This report emphasizes the importance of MRS in evaluating neurological symptoms, broadens the phenotypic spectrum of CRTR and adds knowledge about the pathogenesis of creatine depletion in the brain and retina.

  2. Affected kindred analysis of human X chromosome exomes to identify novel X-linked intellectual disability genes.

    PubMed

    Niranjan, Tejasvi S; Skinner, Cindy; May, Melanie; Turner, Tychele; Rose, Rebecca; Stevenson, Roger; Schwartz, Charles E; Wang, Tao

    2015-01-01

    X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families (a single affected male from 30 families and two affected males from 26 families) using an Agilent SureSelect X-exome kit and the Illumina HiSeq 2000 platform. To enrich for disease-causing mutations, we first utilized variant filters based on dbSNP, the male-restricted portions of the 1000 Genomes Project, or the Exome Variant Server datasets. However, these databases present limitations as automatic filters for enrichment of XLID genes. We therefore developed and optimized a strategy that uses a cohort of affected male kindred pairs and an additional small cohort of affected unrelated males to enrich for potentially pathological variants and to remove neutral variants. This strategy, which we refer to as Affected Kindred/Cross-Cohort Analysis, achieves a substantial enrichment for potentially pathological variants in known XLID genes compared to variant filters from public reference databases, and it has identified novel XLID candidate genes. We conclude that Affected Kindred/Cross-Cohort Analysis can effectively enrich for disease-causing genes in rare, Mendelian disorders, and that public reference databases can be used effectively, but cautiously, as automatic filters for X-linked disorders.

  3. Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family

    PubMed Central

    Kalscheuer, Vera M.; James, Victoria M.; Himelright, Miranda L.; Long, Philip; Oegema, Renske; Jensen, Corinna; Bienek, Melanie; Hu, Hao; Haas, Stefan A.; Topf, Maya; Hoogeboom, A. Jeannette M.; Harvey, Kirsten; Walikonis, Randall; Harvey, Robert J.

    2016-01-01

    Disease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2A789V was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family. PMID:26793055

  4. Report of a kindred with x-linked (or autosomal dominant sex-limited) 46, XY partial gonadal dysgenesis

    SciTech Connect

    Fechner, P.Y.; Marcantonio, S.M.; Ogata, T.; Rosales, T.O.; Smith, K.D.; Goodfellow, P.N.; Migeon, C.J.; Berkovitz, G.D. )

    1993-05-01

    The condition termed 46, XY complete gonadal dysgenesis is characterized by the lack of testicular determination with resulting streak gonads, normal Mullerian structures, and female external genitalia. In the partial form, there is incomplete testicular determination with a wide range in the degree of ambiguous genitalia and sexual duct development. The authors evaluated a kindred in which a partial form of 46, XY gonadal dysgenesis occurred in four subjects from two generations. Pedigree analysis indicated an X-linked or possibly an autosomal sex-limited mode of inheritance. All affected subjects were ascertained because of ambiguous genitalia with minimal virilization. At 10 days of age, the proband had a subnormal plasma level of testosterone, and at 4 months, there was no rise in plasma T after stimulation with hCG. At laparotomy, a dysgenetic gonad was found on the right side, but no gonad was found on the left side. A vas deferens was present on the right, indicating the presence of functional leydig cells early in fetal life. In the other affected subjects, gonadal tissue was also limited to one side of the abdomen and showed poorly developed seminiferous tubules. The sex-determining region Y gene, which encodes the testis-determining factor, was present and unaltered in the genomic DNA of all affected subjects. Duplication of the distal short arm of the X-chromosome has been associated with 46, XY complete gonadal dysgenesis in some patients. In the authors studies, Southern blot analysis revealed that sequences of the distal short arm of the X-chromosome were present in single copy, excluding a large duplication in this area of the X. Several kindreds with familial 46, XY complete gonadal dysgenesis have been reported; five of them had evidence of an X-linked mode of inheritance. The authors study of a kindred with 46, XY partial gonadal dysgenesis further supports the role of an X chromosome gene in testicular determination. 44 refs., 1 fig., 3 tabs.

  5. Donor Splice-Site Mutation in CUL4B is Likely Cause of X-Linked Intellectual Disability

    PubMed Central

    Londin, Eric R.; Adijanto, Jeffrey; Philp, Nancy; Novelli, Antonio; Vitale, Emilia; Perria, Chiara; Serra, Gigliola; Alesi, Viola; Surrey, Saul; Fortina, Paolo

    2015-01-01

    X-linked intellectual disability is the most common form of cognitive disability in males. Syndromic intellectual disability encompasses cognitive deficits with other medical and behavioral manifestations. Recently, a large family with a novel form of syndromic X-linked intellectual disability was characterized. Eight of 24 members of the family are male and had cognitive dysfunction, short stature, aphasia, skeletal abnormalities, and minor anomalies. To identify the causative gene(s), we performed exome sequencing in three affected boys, both parents, and an unaffected sister. We identified a haplotype consisting of eight variants located in cis within the linkage region that segregated with affected members in the family. Of these variants, two were novel. The first was at the splice-donor site of intron 7 (c.974+1G>T) in the cullin-RING ubiquitin ligase (E3) gene, CUL4B. This variant is predicted to result in failure to splice and remove intron 7 from the primary transcript. The second variant mapped to the 3′-UTR region of the KAISO gene (c.1127T>G). Sanger sequencing validated the variants in these relatives as well as in three affected males and five carriers. The KAISO gene variant was predicted to create a binding site for the microRNAs miR-4999 and miR-4774; however, luciferase expression assays failed to validate increased targeting of these miRNAs to the variant 3′-UTR. This SNP may affect 3′-UTR structure leading to decreased mRNA stability. Our results suggest that the intellectual disability phenotype in this family is caused by aberrant splicing and removal of intron 7 from CUL4B gene primary transcript. PMID:24898194

  6. Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia.

    PubMed

    McKee, Marc D; Hoac, Betty; Addison, William N; Barros, Nilana M T; Millán, José L; Chaussain, Catherine

    2013-10-01

    As broadly demonstrated for the formation of a functional skeleton, proper mineralization of periodontal alveolar bone and teeth - where calcium phosphate crystals are deposited and grow within an extracellular matrix - is essential for dental function. Mineralization defects in tooth dentin and cementum of the periodontium invariably lead to a weak (soft or brittle) dentition in which teeth become loose and prone to infection and are lost prematurely. Mineralization of the extremities of periodontal ligament fibers (Sharpey's fibers) where they insert into tooth cementum and alveolar bone is also essential for the function of the tooth-suspensory apparatus in occlusion and mastication. Molecular determinants of mineralization in these tissues include mineral ion concentrations (phosphate and calcium), pyrophosphate, small integrin-binding ligand N-linked glycoproteins and matrix vesicles. Amongst the enzymes important in regulating these mineralization determinants, two are discussed at length here, with clinical examples given, namely tissue-nonspecific alkaline phosphatase and phosphate-regulating gene with homologies to endopeptidases on the X chromosome. Inactivating mutations in these enzymes in humans and in mouse models lead to the soft bones and teeth characteristic of hypophosphatasia and X-linked hypophosphatemia, respectively, where the levels of local and systemic circulating mineralization determinants are perturbed. In X-linked hypophosphatemia, in addition to renal phosphate wasting causing low circulating phosphate levels, phosphorylated mineralization-regulating small integrin-binding ligand N-linked glycoproteins, such as matrix extracellular phosphoglycoprotein and osteopontin, and the phosphorylated peptides proteolytically released from them, such as the acidic serine- and aspartate-rich-motif peptide, may accumulate locally to impair mineralization in this disease.

  7. Affected Kindred Analysis of Human X Chromosome Exomes to Identify Novel X-Linked Intellectual Disability Genes

    PubMed Central

    Niranjan, Tejasvi S.; Skinner, Cindy; May, Melanie; Turner, Tychele; Rose, Rebecca; Stevenson, Roger; Schwartz, Charles E.; Wang, Tao

    2015-01-01

    X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families (a single affected male from 30 families and two affected males from 26 families) using an Agilent SureSelect X-exome kit and the Illumina HiSeq 2000 platform. To enrich for disease-causing mutations, we first utilized variant filters based on dbSNP, the male-restricted portions of the 1000 Genomes Project, or the Exome Variant Server datasets. However, these databases present limitations as automatic filters for enrichment of XLID genes. We therefore developed and optimized a strategy that uses a cohort of affected male kindred pairs and an additional small cohort of affected unrelated males to enrich for potentially pathological variants and to remove neutral variants. This strategy, which we refer to as Affected Kindred/Cross-Cohort Analysis, achieves a substantial enrichment for potentially pathological variants in known XLID genes compared to variant filters from public reference databases, and it has identified novel XLID candidate genes. We conclude that Affected Kindred/Cross-Cohort Analysis can effectively enrich for disease-causing genes in rare, Mendelian disorders, and that public reference databases can be used effectively, but cautiously, as automatic filters for X-linked disorders. PMID:25679214

  8. Novel X-Linked Genes Revealed by Quantitative Polymerase Chain Reaction in the Green Anole, Anolis carolinensis

    PubMed Central

    Rovatsos, Michail; Altmanová, Marie; Pokorná, Martina Johnson; Kratochvíl, Lukáš

    2014-01-01

    The green anole, Anolis carolinensis (ACA), is the model reptile for a vast array of biological disciplines. It was the first nonavian reptile to have its genome fully sequenced. During the genome project, the XX/XY system of sex chromosomes homologous to chicken chromosome 15 (GGA15) was revealed, and 106 X-linked genes were identified. We selected 38 genes located on eight scaffolds in ACA and having orthologs located on GGA15, then tested their linkage to ACA X chromosome by using comparative quantitative fluorescent real-time polymerase chain reaction applied to male and female genomic DNA. All tested genes appeared to be X-specific and not present on the Y chromosome. Assuming that all genes located on these scaffolds should be localized to the ACA X chromosome, we more than doubled the number of known X-linked genes in ACA, from 106 to 250. While demonstrating that the gene content of chromosome X in ACA and GGA15 is largely conserved, we nevertheless showed that numerous interchromosomal rearrangements had occurred since the splitting of the chicken and anole evolutionary lineages. The presence of many ACA X-specific genes localized to distinct contigs indicates that the ACA Y chromosome should be highly degenerated, having lost a large amount of its original gene content during evolution. The identification of novel genes linked to the X chromosome and absent on the Y chromosome in the model lizard species contributes to ongoing research as to the evolution of sex determination in reptiles and provides important information for future comparative and functional genomics. PMID:25172916

  9. The X-files of inflammation: cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection.

    PubMed

    Spolarics, Zoltán

    2007-06-01

    Females as compared with males display better general health status, longevity, and improved clinical course after injury and infection. It is generally believed that the female advantage is associated with the effects of sex hormones. This review argues that the sex benefit of females during the host response is associated with polymorphism of X-linked genes and cellular mosaicism for X-linked parental alleles. Cells from females carry both parental X chromosomes (maternal, Xm; or paternal, Xp), whereas males carry only one (Xm). Because of dosage compensation and random X inactivation, half of the cells from females express either Xm or Xp. Therefore, females are cellular mosaics for their X-linked polymorphic genes. This cellular mosaicism in females represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response. Several genes encoding key metabolic and regulatory proteins reside on the X chromosome, including members of the apoptotic cascade, hormone homeostasis, glucose metabolic enzymes, superoxide-producing machinery, and the toll-like receptor/nuclear factor kappaB/c-Jun N-terminal kinase signaling pathway. Polymorphic forms of these X-linked proteins are likely to manifest in phenotypic differences in the mosaic cell populations in females and may contribute to sex-related differences in the host response to injury and infection. The unique inheritance pattern of X-linked polymorphisms and their potential confounding effects in clinical trials are also discussed; furthermore, we present potential biomarkers for studying mosaic cell populations of innate immunity.

  10. Canine leishmaniosis in South America

    PubMed Central

    Dantas-Torres, Filipe

    2009-01-01

    Canine leishmaniosis is widespread in South America, where a number of Leishmania species have been isolated or molecularly characterised from dogs. Most cases of canine leishmaniosis are caused by Leishmania infantum (syn. Leishmania chagasi) and Leishmania braziliensis. The only well-established vector of Leishmania parasites to dogs in South America is Lutzomyia longipalpis, the main vector of L. infantum, but many other phlebotomine sandfly species might be involved. For quite some time, canine leishmaniosis has been regarded as a rural disease, but nowadays it is well-established in large urbanised areas. Serological investigations reveal that the prevalence of anti-Leishmania antibodies in dogs might reach more than 50%, being as high as 75% in highly endemic foci. Many aspects related to the epidemiology of canine leishmaniosis (e.g., factors increasing the risk disease development) in some South American countries other than Brazil are poorly understood and should be further studied. A better understanding of the epidemiology of canine leishmaniosis in South America would be helpful to design sustainable control and prevention strategies against Leishmania infection in both dogs and humans. PMID:19426440

  11. Stratum corneum lipids in disorders of cornification. Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis.

    PubMed Central

    Elias, P M; Williams, M L; Maloney, M E; Bonifas, J A; Brown, B E; Grayson, S; Epstein, E H

    1984-01-01

    The pathological scaling in recessive x-linked ichthyosis is associated with accumulation of abnormal quantities of cholesterol sulfate in stratum corneum (J. Clin. Invest. 68:1404-1410, 1981). To determine whether or not cholesterol sulfate accumulates in recessive x-linked ichthyosis as a direct result of the missing enzyme, steroid sulfatase, we quantitated both steroid sulfatase and its substrate, we quantitated both steroid sulfatase and its substrate, cholesterol sulfate, in different epidermal strata, as well as within stratum corneum subcellular fractions obtained from normal human and neonatal mouse epidermis and from patients with recessive x-linked ichthyosis. In normal human and mouse epidermis, steroid sulfatase activity peaked in the stratum granulosum and stratum corneum, and negligible activity was detectable in lower epidermal layers. In contrast, in recessive x-linked ichthyosis epidermis, enzyme levels were virtually undetectable at all levels. In normal human stratum corneum, up to 10 times more steroid sulfatase activity was present in purified peripheral membrane preparations than in the whole tissue. Whereas in normal human epidermis cholesterol sulfate levels were lowest in the basal/spinous layer, and highest in the stratum granulosum, in recessive x-linked ichthyosis the levels were only slightly higher in the lower epidermis, but continued to climb in the stratum corneum. In both normal and in recessive x-linked ichthyosis stratum corneum, cholesterol sulfate appeared primarily within membrane domains, paralleling the pattern of steroid sulfatase localization. Finally, the role of excess cholesterol sulfate in the pathogenesis of recessive x-linked ichthyosis was directly tested by topical applications of this substance, which produced visible scaling in hairless mice in parallel to an increased cholesterol sulfate content of the stratum corneum. These results demonstrate an intimate relationship between steroid sulfatase and cholesterol

  12. SAP gene transfer restores cellular and humoral immune function in a murine model of X-linked lymphoproliferative disease.

    PubMed

    Rivat, Christine; Booth, Claire; Alonso-Ferrero, Maria; Blundell, Michael; Sebire, Neil J; Thrasher, Adrian J; Gaspar, H Bobby

    2013-02-14

    X-linked lymphoproliferative disease (XLP1) arises from mutations in the gene encoding SLAM-associated protein (SAP) and leads to abnormalities of NKT-cell development, NK-cell cytotoxicity, and T-dependent humoral function. Curative treatment is limited to allogeneic hematopoietic stem cell (HSC) transplantation. We tested whether HSC gene therapy could correct the multilineage defects seen in SAP(-/-) mice. SAP(-/-) murine HSCs were transduced with lentiviral vectors containing either SAP or reporter gene before transplantation into irradiated recipients. NKT-cell development was significantly higher and NK-cell cytotoxicity restored to wild-type levels in mice receiving the SAP vector in comparison to control mice. Baseline immunoglobulin levels were significantly increased and T-dependent humoral responses to NP-CGG, including germinal center formation, were restored in SAP-transduced mice.We demonstrate for the first time that HSC gene transfer corrects the cellular and humoral defects in SAP(-/-) mice providing proof of concept for gene therapy in XLP1.

  13. MicroRNAs and intellectual disability (ID) in Down syndrome, X-linked ID, and Fragile X syndrome

    PubMed Central

    Siew, Wei-Hong; Tan, Kai-Leng; Babaei, Maryam Abbaspour; Cheah, Pike-See; Ling, King-Hwa

    2013-01-01

    Intellectual disability (ID) is one of the many features manifested in various genetic syndromes leading to deficits in cognitive function among affected individuals. ID is a feature affected by polygenes and multiple environmental factors. It leads to a broad spectrum of affected clinical and behavioral characteristics among patients. Until now, the causative mechanism of ID is unknown and the progression of the condition is poorly understood. Advancement in technology and research had identified various genetic abnormalities and defects as the potential cause of ID. However, the link between these abnormalities with ID is remained inconclusive and the roles of many newly discovered genetic components such as non-coding RNAs have not been thoroughly investigated. In this review, we aim to consolidate and assimilate the latest development and findings on a class of small non-coding RNAs known as microRNAs (miRNAs) involvement in ID development and progression with special focus on Down syndrome (DS) and X-linked ID (XLID) [including Fragile X syndrome (FXS)]. PMID:23596395

  14. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

    PubMed

    Bichet, Daniel G; Bockenhauer, Detlef

    2016-03-01

    Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration.

  15. Bone mineral density of the spine and radius shaft in children with X-linked hypophosphatemic rickets (XLH).

    PubMed

    Oliveri, M B; Cassinelli, H; Bergadá, C; Mautalen, C A

    1991-02-01

    X-linked hypophosphatemic rickets (XLH) is characterized by inadequate skeletal mineralization. The bone mineral density (BMD) of the radius shaft and the lumbar spine was determined in 13 children with XLH. Ten patients were on treatment, whereas three patients had discontinued treatment 20-32 months prior to this study. Two of them had radiological evidence of rickets. The radius shaft BMD was significantly diminished: Z score was -1.33 +/- 0.89 (P less than 0.001), while the BMD of lumbar spine was significantly augmented (Z score +1.95 +/- 1.17, P less than 0.001). A positive correlation was found between the Z scores for the BMD of the radius shaft and spine. The two patients with overt rickets had lower radius shaft BMD values and a lesser increment of BMD of the spine. The BMD deficit of cortical bone may be related to the lack of efficacy of the treatment and/or to an intrinsic defect of the bone on this disease. On the other hand, the augmented BMD of the lumbar spine might reflect the overabundance of partially mineralized osteoid. The determination of the BMD of the radius shaft by SPA was a sensitive method for detecting abnormalities of the bone mass in XLH patients under treatment without radiological signs of rickets.

  16. Importance of B cell co-stimulation in CD4+ T cell differentiation: X-linked agammaglobulinaemia, a human model

    PubMed Central

    Martini, H; Enright, V; Perro, M; Workman, S; Birmelin, J; Giorda, E; Quinti, I; Lougaris, V; Baronio, M; Warnatz, K; Grimbacher, B

    2011-01-01

    We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinaemia. Sixteen patients with X-linked agammaglobulinaemia (XLA) due to mutations in Btk, nine patients affected by common variable immune deficiency (CVID) with <2% of peripheral B cells and 20 healthy volunteers were enrolled. The T cell phenotype was determined with FACSCalibur and CellQuest Pro software. Mann–Whitney two-tailed analysis was used for statistical analysis. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4+CD45RO+ and CD4+CD45RO+CXCR5+ cells and both subsets were decreased significantly when compared to healthy controls: P = 0·001 and P < 0·0001, respectively. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the observed paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans. PMID:21488866

  17. Importance of B cell co-stimulation in CD4(+) T cell differentiation: X-linked agammaglobulinaemia, a human model.

    PubMed

    Martini, H; Enright, V; Perro, M; Workman, S; Birmelin, J; Giorda, E; Quinti, I; Lougaris, V; Baronio, M; Warnatz, K; Grimbacher, B

    2011-06-01

    We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinaemia. Sixteen patients with X-linked agammaglobulinaemia (XLA) due to mutations in Btk, nine patients affected by common variable immune deficiency (CVID) with <2% of peripheral B cells and 20 healthy volunteers were enrolled. The T cell phenotype was determined with FACSCalibur and CellQuest Pro software. Mann-Whitney two-tailed analysis was used for statistical analysis. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4(+)CD45RO(+) and CD4(+)CD45RO(+)CXCR5(+) cells and both subsets were decreased significantly when compared to healthy controls: P = 0·001 and P < 0·0001, respectively. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the observed paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans.

  18. Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy

    PubMed Central

    Lawlor, Michael W.; Armstrong, Dustin; Viola, Marissa G.; Widrick, Jeffrey J.; Meng, Hui; Grange, Robert W.; Childers, Martin K.; Hsu, Cynthia P.; O'Callaghan, Michael; Pierson, Christopher R.; Buj-Bello, Anna; Beggs, Alan H.

    2013-01-01

    No effective treatment exists for patients with X-linked myotubular myopathy (XLMTM), a fatal congenital muscle disease caused by deficiency of the lipid phosphatase, myotubularin. The Mtm1δ4 and Mtm1 p.R69C mice model severely and moderately symptomatic XLMTM, respectively, due to differences in the degree of myotubularin deficiency. Contractile function of intact extensor digitorum longus (EDL) and soleus muscles from Mtm1δ4 mice, which produce no myotubularin, is markedly impaired. Contractile forces generated by chemically skinned single fiber preparations from Mtm1δ4 muscle were largely preserved, indicating that weakness was largely due to impaired excitation contraction coupling. Mtm1 p.R69C mice, which produce small amounts of myotubularin, showed impaired contractile function only in EDL muscles. Short-term replacement of myotubularin with a prototypical targeted protein replacement agent (3E10Fv-MTM1) in Mtm1δ4 mice improved contractile function and muscle pathology. These promising findings suggest that even low levels of myotubularin protein replacement can improve the muscle weakness and reverse the pathology that characterizes XLMTM. PMID:23307925

  19. Prolonged activation of the hypothalamus-pituitary-gonadal axis in a child with X-linked adrenal hypoplasia congenita.

    PubMed

    Takahashi, I; Takahashi, T; Shoji, Y; Takada, G

    2000-07-01

    X-linked adrenal hypoplasia congenita (AHC) is a rare developmental disorder of the human adrenal cortex that is caused by a mutation of the DAX-1 gene, a member of the nuclear hormone receptor superfamily. Hypogonadotrophic hypogonadism is frequently associated with this disease and the DAX-1 mutation is known to impair gonadotrophin production by acting at both the hypothalamic and pituitary levels. However, three recent studies reported that the hypothalamic-pituitary-gonadal axis was active in six infants with AHC, suggesting that a difference exists in the central regulation of hypothalamic-pituitary-gonadal activity between infant boys and pubertal boys. To determine the effect of the DAX-1 gene mutation on the axis in early childhood, we measured testosterone, LH, and FSH and performed LH-releasing hormone tests on a boy with AHC from birth to 3 years of age. Surprisingly, our findings showed that the axis was active from the infantile period to 3 years of age. This delayed initiation of the prepubertal pause, or prolonged activation of the axis, indicates that the DAX-1 gene is related to the control mechanism of the prepubertal restraint of gonadotrophin secretion.

  20. Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting.

    PubMed

    Longo, Nancy S; Lugar, Patricia L; Yavuz, Sule; Zhang, Wen; Krijger, Peter H L; Russ, Daniel E; Jima, Dereje D; Dave, Sandeep S; Grammer, Amrie C; Lipsky, Peter E

    2009-04-16

    Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27(+) memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.

  1. Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting

    PubMed Central

    Longo, Nancy S.; Lugar, Patricia L.; Yavuz, Sule; Zhang, Wen; Krijger, Peter H. L.; Russ, Daniel E.; Jima, Dereje D.; Dave, Sandeep S.; Grammer, Amrie C.

    2009-01-01

    Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27+ memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity. PMID:19023113

  2. A Splice Defect in the EDA Gene in Dogs with an X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Phenotype

    PubMed Central

    Waluk, Dominik P.; Zur, Gila; Kaufmann, Ronnie; Welle, Monika M.; Jagannathan, Vidhya; Drögemüller, Cord; Müller, Eliane J.; Leeb, Tosso; Galichet, Arnaud

    2016-01-01

    X-linked hypohidrotic ectodermal dysplasia (XLHED) caused by variants in the EDA gene represents the most common ectodermal dysplasia in humans. We investigated three male mixed-breed dogs with an ectodermal dysplasia phenotype characterized by marked hypotrichosis and multifocal complete alopecia, almost complete absence of sweat and sebaceous glands, and altered dentition with missing and abnormally shaped teeth. Analysis of SNP chip genotypes and whole genome sequence data from the three affected dogs revealed that the affected dogs shared the same haplotype on a large segment of the X-chromosome, including the EDA gene. Unexpectedly, the whole genome sequence data did not reveal any nonsynonymous EDA variant in the affected dogs. We therefore performed an RNA-seq experiment on skin biopsies to search for changes in the transcriptome. This analysis revealed that the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. These dogs thus offer an excellent opportunity to gain insights into the complex splicing processes required for expression of the EDA gene, and other genes with large introns. PMID:27449516

  3. X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

    PubMed Central

    Madrigal, I; Rodríguez-Revenga, L; Armengol, L; González, E; Rodriguez, B; Badenas, C; Sánchez, A; Martínez, F; Guitart, M; Fernández, I; Arranz, JA; Tejada, MI; Pérez-Jurado, LA; Estivill, X; Milà, M

    2007-01-01

    Background Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. Results Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%). Conclusion This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients. PMID:18047645

  4. The nuclear receptor NOR-1 regulates the small muscle protein, X-linked (SMPX) and myotube differentiation

    PubMed Central

    Ferrán, Beatriz; Martí-Pàmies, Ingrid; Alonso, Judith; Rodríguez-Calvo, Ricardo; Aguiló, Silvia; Vidal, Francisco; Rodríguez, Cristina; Martínez-González, José

    2016-01-01

    Recent works have highlighted the role of NOR-1 in both smooth and skeletal muscle, and have proposed this nuclear receptor as a nexus that coordinates muscle performance and metabolic capacity. However, no muscle specific genes regulated by NOR-1 have been identified so far. To identify NOR-1 target genes, we over-expressed NOR-1 in human vascular smooth muscle cells (VSMC). These cells subjected to sustained over-expression of supraphysiological levels of NOR-1 experienced marked phenotypic changes and up-regulated the skeletal muscle protein X-linked (SMPX), a protein typically expressed in striated muscle and associated to cell shape. By transcriptional studies and DNA-protein binding assays, we identified a non-consensus NBRE site in human SMPX promoter, critical for NOR-1 responsiveness. The expression of SMPX was higher in human skeletal muscle myoblasts (HSMM) than in human VSMC, and further increased in HSMM differentiated to myotubes. NOR-1 silencing prevented SMPX expression in HSMM, as well as their differentiation to myotubes, but the up-regulation of SMPX was dispensable for HSMM differentiation. Our results indicate that NOR-1 regulate SMPX in human muscle cells and acts as a muscle regulatory factor, but further studies are required to unravel its role in muscle differentiation and hypertrophy. PMID:27181368

  5. The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy

    PubMed Central

    Ofman, Rob; Dijkstra, Inge M E; van Roermund, Carlo W T; Burger, Nena; Turkenburg, Marjolein; van Cruchten, Arno; van Engen, Catherine E; Wanders, Ronald J A; Kemp, Stephan

    2010-01-01

    X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). X-ALD is characterized by the accumulation of very long-chain fatty acids (VLCFA; ≥C24) in plasma and tissues. In this manuscript we provide insight into the pathway underlying the elevated levels of C26:0 in X-ALD. ALDP transports VLCFacyl-CoA across the peroxisomal membrane. A deficiency in ALDP impairs peroxisomal β-oxidation of VLCFA but also raises cytosolic levels of VLCFacyl-CoA which are substrate for further elongation. We identify ELOVL1 (elongation of very-long-chain-fatty acids) as the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1). ELOVL1 expression is not increased in X-ALD fibroblasts suggesting that increased levels of C26:0 result from increased substrate availability due to the primary deficiency in ALDP. Importantly, ELOVL1 knockdown reduces elongation of C22:0 to C26:0 and lowers C26:0 levels in X-ALD fibroblasts. Given the likely pathogenic effects of high C26:0 levels, our findings highlight the potential of modulating ELOVL1 activity in the treatment of X-ALD. PMID:20166112

  6. Early Diagnosis of Cerebral X-linked Adrenoleukodystrophy in Boys with Addison’s Disease Improves Survival and Neurological Outcomes

    PubMed Central

    Polgreen, LE; Chahla, S; Miller, W; Rothman, S.; Tolar, J; Kivisto, T; Nascene, D.; Orchard, PJ; Petryk, A

    2011-01-01

    Approximately one-third of boys with X-linked adrenoleukodystophy (X-ALD) develop an acute, progressive inflammatory process of the central nervous system, resulting in rapid neurologic deterioration and death. Hematopoietic cell transplantation (HCT) can halt the progression of neurologic disease if performed early in the course of the cerebral form of X-ALD. We describe a retrospective cohort study of 90 boys with X-ALD evaluated at our institution between 2000 and 2009, to determine if early diagnosis of X-ALD following the diagnosis of unexplained adrenal insufficiency (AI) improves outcomes. We describe 7 cases with a delay in the diagnosis of X-ALD, and compare their outcomes to 10 controls with the diagnosis of ALD made within 12 months following diagnosis of AI. At the time of evaluation for HCT, boys with a delay in the diagnosis of X-ALD had more extensive cerebral involvement and more limited functioning. These boys also were 3.9 times more likely to die, and had significant advancement of cerebral disease after HCT, compared to boys with a timely diagnosis of X-ALD. Conclusion Early diagnosis of cerebral X-ALD following the diagnosis of unexplained AI, and subsequent treatment with HCT, improves both neurological outcomes and survival in boys with cerebral X-ALD. PMID:21279382

  7. Hexacosanoic and docosanoic acids plasma levels in patients with cerebral childhood and asymptomatic X-linked adrenoleukodystrophy: Lorenzo's oil effect.

    PubMed

    Deon, Marion; Garcia, Mariana Pires; Sitta, Angela; Barschak, Alethéa G; Coelho, Daniella M; Schimit, Graziela O; Pigatto, Maiara; Jardim, Laura B; Wajner, Moacir; Giugliani, Roberto; Vargas, Carmen R

    2008-03-01

    X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal metabolism, biochemically characterized by deficient beta-oxidation of saturated very long chain fatty acids (VLCFA). The consequent accumulation of these fatty acids in different tissues and in biological fluids is associated with a progressive central and peripheral demyelination, as well as with adrenocortical insufficiency and hypogonadism. Seven variants of this disease have been described, cerebral childhood being the most frequent. The recommended therapy consists of the use of the glyceroltrioleate/glyceroltrierucate mixture known as Lorenzo's Oil (LO), combined with a VLCFA-poor diet, but only in asymptomatic patients will this treatment prevent the progression of the symptomatology. In the present study we evaluated the biochemical course of patients with cerebral childhood (CCER) and asymptomatic clinical forms of X-ALD treated with LO associated with a VLCFA-restricted diet. We observed that hexacosanoic acid plasma concentrations and hexacosanoic/docosanoic ratio were significantly reduced in CCER patients during treatment when compared with diagnosis. Hexacosanoic acid plasma level was significantly reduced when compared with that at diagnosis and achieved the normal levels only in asymptomatic patients under LO treatment. In asymptomatic patients the magnitude of hexacosanoic acid decrease was higher than that of the CCER patients. These results show the good biochemical response of LO treatment in asymptomatic X-ALD patients. It is possible to suppose that this could be correlated with the prevention of the appearance of neurological signals in this group of patients treated with LO.

  8. Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice

    PubMed Central

    Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Barbieri, Claudia; Nicoletti, Maria C; H. Li, Jian; Wess, Jürgen; Svelto, Maria

    2014-01-01

    X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI. PMID:24522493

  9. Towards fully automated genotyping: use of an X linked recessive spastic paraplegia family to test alternative analysis methods.

    PubMed

    Kobayashi, H; Matise, T C; Perlin, M W; Marks, H G; Hoffman, E P

    1995-05-01

    Advances in dinucleotide-based genetic maps open possibilities for large scale genotyping at high resolution. The current rate-limiting steps in use of these dense maps is data interpretation (allele definition), data entry, and statistical calculations. We have recently reported automated allele identification methods. Here we show that a 10-cM framework map of the human X chromosome can be analyzed on two lanes of an automated sequencer per individual (10-12 loci per lane). We use this map and analysis strategy to generate allele data for an X-linked recessive spastic paraplegia family with a known PLP mutation. We analyzed 198 genotypes in a single gel and used the data to test three methods of data analysis: manual meiotic breakpoint mapping, automated concordance analysis, and whole chromosome multipoint linkage analysis. All methods pinpointed the correct location of the gene. We propose that multipoint exclusion mapping may permit valid inflation of LOD scores using the equation max LOD-(next best LOD). PMID:7759066

  10. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

    PubMed

    Bichet, Daniel G; Bockenhauer, Detlef

    2016-03-01

    Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration. PMID:27156763

  11. Biochemical characterization of arylsulfatase E and functional analysis of mutations found in patients with X-linked chondrodysplasia punctata.

    PubMed Central

    Daniele, A; Parenti, G; d'Addio, M; Andria, G; Ballabio, A; Meroni, G

    1998-01-01

    X-linked chondrodysplasia punctata (CDPX) is a congenital disorder characterized by abnormalities in cartilage and bone development. Mutations leading to amino acid substitutions were identified recently in CDPX patients, in the coding region of the arylsulfatase E (ARSE) gene, a novel member of the sulfatase gene family. Transfection of the ARSE full-length cDNA, in Cos7 cells, allowed us to establish that its protein product is a 60-kD precursor, which is subject to N-glycosylation, to give a mature 68-kD form that, unique among sulfatases, is localized to the Golgi apparatus. Five missense mutations found in CDPX patients were introduced into wild-type ARSE cDNA by site-directed mutagenesis. These mutants were transfected into Cos7 cells, and the arylsulfatase activity and biochemical properties were determined, to study the effect of these substitutions on the ARSE protein. One of the mutants behaves as the wild-type protein. All four of the other mutations resulted in a complete lack of arylsulfatase activity, although the substitutions do not appear to affect the stability and subcellular localization of the protein. The loss of activity due to these mutations confirms their involvement in the clinical phenotype and points to the importance of these residues in the correct folding of a catalytically active ARSE enzyme. PMID:9497243

  12. Structural and Functional Characteristics in Carriers of X-Linked Retinitis Pigmentosa with a Tapetal-Like Reflex

    PubMed Central

    Genead, Mohamed A.; Fishman, Gerald A.; Lindeman, Martin; affiliation, COMT Institute

    2010-01-01

    Purpose to identify the functional and structural characteristics in three female obligate carriers of X-linked retinitis pigmentosa (XLRP) from the same family by using spectral-domain OCT (SD-OCT), fundus autofluorescence (FAF), and microperimetry (MP). Methods Three female obligate carriers with a tapetal-like reflex (TLR), 21, 49, and 57 years of age, from a single family of XLRP that was seen in the ophthalmology department at the University of Illinois at Chicago, were enrolled in the study. All carriers underwent a complete ophthalmic examination. SD-OCT measurements, a macular MP exam, and FAF testing were performed. Results The SD-OCT exam in all three carriers showed a normal retinal micro-structure and thickness. Microperimeter testing showed subnormal retinal sensitivity in the areas of the TLR. FAF exam showed the presence of speckled areas of enhanced AF. Conclusions Our study demonstrates that the carriers of XLRP with a TLR can show an enhanced reflectance on infrared images, abnormal autofluorescence properties, elevated retinal thresholds, and a normal retinal morphology within the posterior pole on SD-OCT testing PMID:20829740

  13. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease.

    PubMed

    De Ravin, Suk See; Reik, Andreas; Liu, Pei-Qi; Li, Linhong; Wu, Xiaolin; Su, Ling; Raley, Castle; Theobald, Narda; Choi, Uimook; Song, Alexander H; Chan, Andy; Pearl, Jocelynn R; Paschon, David E; Lee, Janet; Newcombe, Hannah; Koontz, Sherry; Sweeney, Colin; Shivak, David A; Zarember, Kol A; Peshwa, Madhusudan V; Gregory, Philip D; Urnov, Fyodor D; Malech, Harry L

    2016-04-01

    Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ∼15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases.

  14. Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice.

    PubMed

    Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Barbieri, Claudia; Nicoletti, Maria C; Li, Jian H; Wess, Jürgen; Svelto, Maria

    2014-07-01

    X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI.

  15. Importance of B cell co-stimulation in CD4(+) T cell differentiation: X-linked agammaglobulinaemia, a human model.

    PubMed

    Martini, H; Enright, V; Perro, M; Workman, S; Birmelin, J; Giorda, E; Quinti, I; Lougaris, V; Baronio, M; Warnatz, K; Grimbacher, B

    2011-06-01

    We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinaemia. Sixteen patients with X-linked agammaglobulinaemia (XLA) due to mutations in Btk, nine patients affected by common variable immune deficiency (CVID) with <2% of peripheral B cells and 20 healthy volunteers were enrolled. The T cell phenotype was determined with FACSCalibur and CellQuest Pro software. Mann-Whitney two-tailed analysis was used for statistical analysis. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4(+)CD45RO(+) and CD4(+)CD45RO(+)CXCR5(+) cells and both subsets were decreased significantly when compared to healthy controls: P = 0·001 and P < 0·0001, respectively. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the observed paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans. PMID:21488866

  16. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry.

    PubMed

    Gross, T G; Filipovich, A H; Conley, M E; Pracher, E; Schmiegelow, K; Verdirame, J D; Vowels, M; Williams, L L; Seemayer, T A

    1996-05-01

    Seven male patients in the David T Purtilo International X-linked Lymphoproliferative Disease (XLP) Registry have undergone allogeneic hematopoietic stem cell transplantation (HSCT). All patients received HSCT from HLA-identical donors: sibling BM, five; unrelated BM, one; and sibling umbilical cord blood, one. Ages at time of HSCT ranged from 5 to 30 years. Pre-HSCT clinical course varied, but four boys had a significant history of chronic and/or serious infections. Conditioning regimens varied: TBI containing regimens, four, chemotherapy only, three. All patients engrafted. Six developed grade I-II acute GVHD but no chronic GVHD. Four are alive and well with normal immune function greater than 3 years following HSCT. Three died within 100 days: disseminated adenovirus, one; polymicrobial sepsis, one; and multiple organ system failure and bleeding diathesis, one. No EBV-associated post-transplant complications were observed, even though all donors except the umbilical cord blood were EBV-seropositive. Unsuccessful HSCT was associated with age at HSCT (> 15 years), TBI-containing regimen and significant history for pre-HSCT infections. These results provide evidence that HSCT performed during childhood with HLA-identical sibling donors, regardless of EBV serostatus, offers the only curative therapy for XLP. PMID:8733691

  17. Forensic potential of the STR DXYS156 in Mexican populations: inference of X-linked allele null.

    PubMed

    Torres-Rodríguez, M; Martínez-Cortes, G; Páez-Riberos, L A; Sandoval, L; Muñoz-Valle, J F; Ceballos-Quintal, J M; Pinto-Escalante, D; Rangel-Villalobos, H

    2006-01-01

    The pentanucleotide STR (TAAAA)n DXYS156 offers advantages for genetic identity testing. In addition to establish the gender, DXYS156 expands the DNA profile and is able to indicate the possible geographic origin of the individual. We analyzed DXYS156 in 757 individuals of both sexes from Mexican populations. We studied the cosmopolitan Mestizo population and six Mexican ethnic groups: Tarahumaras, Purépechas, Nahuas, Mayas, Huicholes and Mezcala Indians. The six shorter (4-10) and the three larger alleles (11-13) were specific for the X and Y-chromosomes, respectively. A random distribution of alleles into genotypes was observed in males and females from each population. We estimated the power of exclusion for paternity testing according to the son's gender, and the power of discrimination in forensic casework. In addition, we detected a relatively high frequency of an X-linked allele null, principally in Mexican-Mestizos (3.6%), which must be considered when DXYS156 be applied for identification purposes.

  18. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease.

    PubMed

    De Ravin, Suk See; Reik, Andreas; Liu, Pei-Qi; Li, Linhong; Wu, Xiaolin; Su, Ling; Raley, Castle; Theobald, Narda; Choi, Uimook; Song, Alexander H; Chan, Andy; Pearl, Jocelynn R; Paschon, David E; Lee, Janet; Newcombe, Hannah; Koontz, Sherry; Sweeney, Colin; Shivak, David A; Zarember, Kol A; Peshwa, Madhusudan V; Gregory, Philip D; Urnov, Fyodor D; Malech, Harry L

    2016-04-01

    Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ∼15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases. PMID:26950749

  19. A Splice Defect in the EDA Gene in Dogs with an X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Phenotype.

    PubMed

    Waluk, Dominik P; Zur, Gila; Kaufmann, Ronnie; Welle, Monika M; Jagannathan, Vidhya; Drögemüller, Cord; Müller, Eliane J; Leeb, Tosso; Galichet, Arnaud

    2016-01-01

    X-linked hypohidrotic ectodermal dysplasia (XLHED) caused by variants in the EDA gene represents the most common ectodermal dysplasia in humans. We investigated three male mixed-breed dogs with an ectodermal dysplasia phenotype characterized by marked hypotrichosis and multifocal complete alopecia, almost complete absence of sweat and sebaceous glands, and altered dentition with missing and abnormally shaped teeth. Analysis of SNP chip genotypes and whole genome sequence data from the three affected dogs revealed that the affected dogs shared the same haplotype on a large segment of the X-chromosome, including the EDA gene. Unexpectedly, the whole genome sequence data did not reveal any nonsynonymous EDA variant in the affected dogs. We therefore performed an RNA-seq experiment on skin biopsies to search for changes in the transcriptome. This analysis revealed that the EDA transcript in the affected dogs lacked 103 nucleotides encoded by exon 2. We speculate that this exon skipping is caused by a genetic variant located in one of the large introns flanking this exon, which was missed by whole genome sequencing with the illumina short read technology. The altered EDA transcript splicing most likely causes the observed ectodermal dysplasia in the affected dogs. These dogs thus offer an excellent opportunity to gain insights into the complex splicing processes required for expression of the EDA gene, and other genes with large introns. PMID:27449516

  20. A gene for nonsyndromic X-linked mental retardation (MRX77) maps to Xq12-Xq21.33.

    PubMed

    Sismani, Carolina; Syrrou, Maria; Christodoulou, Kyproula; Hamel, Ben; Chelly, Jamel; Yntema, Helger G; van Bokhoven, Hans; Tzoufi, Meropi; Georgiou, Ioannis; Patsalis, Philippos C

    2003-09-15

    Nonsyndromic X-linked mental retardation (MRX) is a highly heterogeneous condition in which mental retardation appears to be the only consistent manifestation. According to the most recent data, 77 MRX families with a lod score of >2 have been mapped and eight genes have been cloned. We hereby report on a linkage analysis performed on a Greek family with apparently nonsyndromic MRX. The affected males have moderate to severe mental retardation, severe speech problems, and aggressive behavior. Two-point linkage analysis with 26 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 27 Mb interval in Xq12-Xq21.33. The maximum LOD score was found for markers DXS1225, DXS8114, and DXS990 at 2.36, 2.06, 2.06, respectively at theta = 0.00. Recombination was observed for DXS983 at the proximal side and DXS6799 at the distal side. Nineteen other MRX families have been described with a partial overlapping disease gene interval in proximal Xq. No mutations were found in the MRX77 family for three known or candidate MRX genes, from this region OPHN1, RSK4, and ATR-X. These data indicate that the Xq12-Xq21.33 interval contains at least one additional MRX gene.

  1. Manifestations of X-linked congenital stationary night blindness in three daughters of an affected male: Demonstration of homozygosity

    SciTech Connect

    Bech-Hansen, N.T. Univ. of Calgary, Alberta ); Pearce, W.G. )

    1993-01-01

    X-linked congenital stationary night blindness (CSNB1) is a hereditary retinal disorder in which clinical features in affected males usually include myopia, nystagmus, and impaired visual acuity. Electroretinography demonstrates a marked reduction in b-wave amplitude. In the study of a large Mennonite family with CSNB1, three of five sisters in one sibship were found to have manifestations of CSNB1. All the sons of these three sisters were affected. Each of the two nonmanifesting sisters had at least one unaffected son. Analysis of Xp markers in the region Xp21.1-Xp11.22 showed that the two sisters who were unaffected had inherited the same maternal X chromosome (i.e., M2). Two of the daughters who manifested with CSNB had inherited the other maternal X chromosome (M1). The third manifesting sister inherited a recombinant X chromosome with a crossover between TIMP and DXS255, which suggests that the CSNB1 locus lies proximal to TIMP. One of the affected daughters' sons had inherited the maternal M1 X chromosome, a finding consistent with that chromosome carrying a mutant CSNB gene; the other affected sons inherited the grandfather's X chromosome (i.e., P). Molecular analysis of DNA from three sisters with manifestations of CSNB is consistent with their being homozygous at the CSNB1 locus and with their mother being a carrier of CSNB1. 23 refs., 4 figs., 3 tabs.

  2. A gene (SRPX) encoding a sushi-repeat-containing protein is deleted in patients with X-linked retinitis pigmentosa.

    PubMed

    Meindl, A; Carvalho, M R; Herrmann, K; Lorenz, B; Achatz, H; Lorenz, B; Apfelstedt-Sylla, E; Wittwer, B; Ross, M; Meitinger, T

    1995-12-01

    X-linked retinitis pigmentosa (XLRP) is characterized by retinal degeneration with night blindness and progressive reduction of the visual fields. By linkage and deletion analysis a gene locus (RP3) has been mapped to the short arm of the X chromosome between the genes CYBB and OTC. Analysis of transcript in this region has revealed a gene which is abundantly expressed in human retina and encodes a putative membrane protein with significant homologies to short consensus repeat (SCR/sushi) domains known from selections and complement proteins. The gene termed SRPX (sushi-repeat-containing protein, x chromosome) is deleted in an RP patient who also suffers from chronic granulomatous disease and McLeod syndrome. A 75 kb deletion removing exon 1 of the gene was also found in two brothers of a second XLRP family. However, no further functionally significant mutations were detected by SSCP screening of all 10 exons in 34 unrelated XLRP patients nor by full length RT-PCR sequencing in two RP3 families. The role of this highly conserved retinal gene in the pathogenesis of RP therefore remains to be determined.

  3. X-Linked adrenoleukodystrophy is a frequent cause of idiopathic Addison`s disease in young adult male patients

    SciTech Connect

    Laureti, S.; Casucci, G.; Santeusanio, F.

    1996-02-01

    X-Linked adrenoleukodystrophy (ALD) is a genetic disease associated with demyelination of the central nervous system, adrenal insufficiency, and accumulation of very long chain fatty acids in tissue and body fluids. ALD is due to mutation of a gene located in Xq28 that encodes a peroxisomal transporter protein of unknown function. The most common phenotype of ALD is the cerebral form (45%) that develops in boys between 5-12 yr. Adrenomyeloneuropathy (AMN) involves the spinal cord and peripheral nerves in young adults (35%). Adrenal insufficiency (Addison`s disease) is frequently associated with AMN or cerebral ALD and may remain the only clinical expression of ALD (8% of cases). The prevalence of ALD among adults with Addison`s disease remains unknown. To evaluate this prevalence, we performed biochemical analysis of very long chain fatty acids in 14 male patients (age ranging from 12-45 yr at diagnosis) previously diagnosed as having primary idiopathic adrenocortical insufficiency. In 5 of 14 patients (35%), elevated plasma concentrations of very long chain fatty acids were detected. None of these patients had adrenocortical antibodies. By electrophysiological tests and magnetic resonance imaging it was determined that two patients had cerebral ALD, one had adrenomyeloneuropathy with cerebral involvement, and two had preclinical AMN. Our data support the hypothesis that ALD is a frequent cause of idiopathic Addison`s disease in children and adults. 30 refs., 5 tabs.

  4. New mutations of DAX-1 genes in two Japanese patients with X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism

    SciTech Connect

    Yanase, Toshihiko; Takayanagi, Ryoichi; Oba, Koichi

    1996-02-01

    Congenital adrenal hypoplasia, an X-linked disorder, is characterized by primary adrenal insufficiency and frequent association with hypogonadotropic hypogonadism. The X-chromosome gene DAX-1 has been most recently identified and shown to be responsible for this disorder. We analyzed the DAX-1 genes of two unrelated Japanese patients with congenital adrenal hypoplasia and hypogonadotropic hypogonadism by using PCR amplification of genomic DNA and its complete exonic sequencing. In a family containing several affected individuals, the proband male patient had a stop codon (TGA) in place of tryptophan (TGG) at amino acid position 171. As expected, his mother was a heterozygous carrier for the mutation, whereas his father and unaffected brother did not carry this mutation. In another male patient with noncontributory family history, sequencing revealed a 1-bp (T) deletion at amino acid position 280, leading to a frame shift and, subsequently a premature stop codon at amino acid position 371. The presence of this mutation in the patients` genome was further confirmed by digestion of genomic PCR product with MspI created by this mutation. Family studies using MspI digestion of genomic PCR products revealed that neither parent of this individual carried the mutation. These results clearly indicate that congenital adrenal hypoplasia and hypogonadotropic hypogonadism result from not only inherited but also de novo mutation in the DAX-1 gene. 31 refs., 4 figs., 2 tabs.

  5. Genetic Testing Confirmed the Early Diagnosis of X-Linked Hypophosphatemic Rickets in a 7-Month-Old Infant

    PubMed Central

    Poon, Kok Siong; Sng, Andrew Anjian; Ho, Cindy Weili; Koay, Evelyn Siew-Chuan

    2015-01-01

    Loss-of-function mutations in the phosphate regulating gene with homologies to endopeptidases on the X-chromosome (PHEX) have been causally associated with X-linked hypophosphatemic rickets (XLHR). The early diagnosis of XLHR in infants is challenging when it is based solely on clinical features and biochemical findings. We report a 7-month-old boy with a family history of hypophosphatemic rickets., who demonstrated early clinical evidence of rickets, although serial biochemical findings could not definitively confirm rickets. A sequencing assay targeting the PHEX gene was first performed on the mother’s DNA to screen for mutations in the 5′UTR, 22 coding exons, and the exon-intron junctions. Targeted mutation analysis and mRNA studies were subsequently performed on the boys’ DNA to investigate the pathogenicity of the identified mutation. Genetic screening of the PHEX gene revealed a novel mutation, c.1080-2A>C, at the splice acceptor site in intron 9. The detection of an aberrant mRNA transcript with skipped (loss of) exon 10 establishes its pathogenicity and confirms the diagnosis of XLHR in this infant. Genetic testing of the PHEX gene resulted in early diagnosis of XLHR, thus enabling initiation of therapy and prevention of progressive rachitic changes in the infant. PMID:26904698

  6. C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man

    PubMed Central

    van de Beek, Malu-Clair; Dijkstra, Inge M. E.; van Lenthe, Henk; Ofman, Rob; Goldhaber-Pasillas, Dalia; Schauer, Nicolas; Schackmann, Martin; Engelen-Lee, Joo-Yeon; Vaz, Frédéric M.; Kulik, Wim; Wanders, Ronald J. A.; Engelen, Marc; Kemp, Stephan

    2016-01-01

    X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. Virtually all males develop progressive myelopathy (AMN). A subset of patients, however, develops a fatal cerebral demyelinating disease (cerebral ALD). Hematopoietic stem cell transplantation is curative for cerebral ALD provided the procedure is performed in an early stage of the disease. Unfortunately, this narrow therapeutic window is often missed. Therefore, an increasing number of newborn screening programs are including ALD. To identify new biomarkers for ALD, we developed an Abcd1 knockout mouse with enhanced VLCFA synthesis either ubiquitous or restricted to oligodendrocytes. Biochemical analysis revealed VLCFA accumulation in different lipid classes and acylcarnitines. Both C26:0-lysoPC and C26:0-carnitine were highly elevated in brain, spinal cord, but also in bloodspots. We extended the analysis to patients and confirmed that C26:0-carnitine is also elevated in bloodspots from ALD patients. We anticipate that validation of C26:0-carnitine for the diagnosis of ALD in newborn bloodspots may lead to a faster inclusion of ALD in newborn screening programs in countries that already screen for other inborn errors of metabolism. PMID:27124591

  7. Current developments in canine genetics.

    PubMed

    Marschall, Yvonne; Distl, Ottmar

    2010-01-01

    In recent years, canine genetics had made huge progress. In 1999 the first complete karyotype and ideogram of the dog was published. Several linkage and RH maps followed. Using these maps, sets of microsatellite markers for whole genome scans were compiled. In 2003 the sequencing of the DNA of a female Boxer began. Now the second version of the dog genome assembly has been put online, and recently, a microchip SNP array became available. Parallel to these developments, some causal mutations for different traits have been identified. Most of the identified mutations were responsible for monogenic canine hereditary diseases. With the tools available now, it is possible to use the advantages of the population structure of the various dog breeds to unravel complex genetic traits. Furthermore, the dog is a suitable model for the research of a large number of human hereditary diseases and particularly for cancer genetics, heart and neurodegenerative diseases. There are some examples where it was possible to benefit from the knowledge of canine genetics for human research. The search for quantitative trait loci (QTL), the testing of candidate genes and genome-wide association studies can now be performed in dogs. QTL for skeletal size variations and for canine hip dysplasia have been already identified and for these complex traits the responsible genes and their possible interactions can now be identified. PMID:20690545

  8. Nonsyndromic X-linked intellectual deficiency in three brothers with a novel MED12 missense mutation [c.5922G>T (p.Glu1974His)

    PubMed Central

    Bouazzi, Habib; Lesca, Gaetan; Trujillo, Carlos; Alwasiyah, Mohammad Khalid; Munnich, Arnold

    2015-01-01

    Key Clinical Message X-linked intellectual deficiency (XLID) is a large group of genetic disorders. MED12 gene causes syndromic and nonsyndromic forms of XLID. Only seven pathological mutations have been identified in this gene. Here, we report a novel mutation segregating with XLID phenotype. This mutation could be in favor of genotype–phenotype correlations. PMID:26273451

  9. X-inactivation patterns in female Leber`s hereditary optic neuropathy patients do not support a strong X-linked determinant

    SciTech Connect

    Pegoraro, E.; Hoffman, E.P.; Carelli, V.; Cortelli, P.

    1996-02-02

    Leber`s hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model of mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. 39 refs., 2 figs., 1 tab.

  10. CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restori...

  11. Nonsyndromic X-linked intellectual deficiency in three brothers with a novel MED12 missense mutation [c.5922G>T (p.Glu1974His)].

    PubMed

    Bouazzi, Habib; Lesca, Gaetan; Trujillo, Carlos; Alwasiyah, Mohammad Khalid; Munnich, Arnold

    2015-07-01

    X-linked intellectual deficiency (XLID) is a large group of genetic disorders. MED12 gene causes syndromic and nonsyndromic forms of XLID. Only seven pathological mutations have been identified in this gene. Here, we report a novel mutation segregating with XLID phenotype. This mutation could be in favor of genotype-phenotype correlations. PMID:26273451

  12. Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3

    PubMed Central

    Solomon, N; Ross, S; Morgan, T; Belsky, J; Hol, F; Karnes, P; Hopwood, N; Myers, S; Tan, A; Warne, G; Forrest, S; Thomas, P

    2004-01-01

    Introduction: Array comparative genomic hybridisation (array CGH) is a powerful method that detects alteration of gene copy number with greater resolution and efficiency than traditional methods. However, its ability to detect disease causing duplications in constitutional genomic DNA has not been shown. We developed an array CGH assay for X linked hypopituitarism, which is associated with duplication of Xq26–q27. Methods: We generated custom BAC/PAC arrays that spanned the 7.3 Mb critical region at Xq26.1–q27.3, and used them to search for duplications in three previously uncharacterised families with X linked hypopituitarism. Results: Validation experiments clearly identified Xq26–q27 duplications that we had previously mapped by fluorescence in situ hybridisation. Array CGH analysis of novel XH families identified three different Xq26–q27 duplications, which together refine the critical region to a 3.9 Mb interval at Xq27.2–q27.3. Expression analysis of six orthologous mouse genes from this region revealed that the transcription factor Sox3 is expressed at 11.5 and 12.5 days after conception in the infundibulum of the developing pituitary and the presumptive hypothalamus. Discussion: Array CGH is a robust and sensitive method for identifying X chromosome duplications. The existence of different, overlapping Xq duplications in five kindreds indicates that X linked hypopituitarism is caused by increased gene dosage. Interestingly, all X linked hypopituitarism duplications contain SOX3. As mutation of this gene in human beings and mice results in hypopituitarism, we hypothesise that increased dosage of Sox3 causes perturbation of pituitary and hypothalamic development and may be the causative mechanism for X linked hypopituitarism. PMID:15342697

  13. Human Erythroid 5-Aminolevulinate Synthase Mutations Associated with X-Linked Protoporphyria Disrupt Conformational Equilibrium and Enhance Product Release†

    PubMed Central

    Fratz, Erica J.; Clayton, Jerome; Hunter, Gregory A.; Ducamp, Sarah; Breydo, Leonid; Uversky, Vladimir N.; Deybach, Jean-Charles; Gouya, Laurent; Puy, Hervé; Ferreira, Gloria C.

    2015-01-01

    Regulation of 5-aminolevulinate synthase (ALAS) is at the origin of balanced heme production in mammals. Mutations in the C-terminal region of human erythroid-specific ALAS (hALAS2) are associated with X-linked protoporphyria (XLPP), a disease characterized by extreme photosensitivity, with elevated blood concentrations of free protoporphyrin IX and zinc protoporphyrin. To investigate the molecular basis for this disease, recombinant hALAS2 and variants of the enzyme harboring the gain-of-function XLPP mutations were constructed, purified, and analyzed kinetically, spectroscopically and thermodynamically. Enhanced activities of the XLPP variants resulted from accelerations in the rate at which the product 5-aminolevulinate (ALA) was released from the enzyme. Circular dichroism spectroscopy revealed that the XLPP mutations altered the microenvironment of the pyridoxal 5’-phosphate cofactor, which underwent further and specific alterations upon succinyl-CoA binding. Transient kinetic analyses of the variant-catalyzed reactions and protein fluorescence quenching upon ALA binding to the XLPP variants demonstrated that the protein conformational transition step associated with product release was predominantly affected. Of relevance, XLPP could also be modeled in cell culture. We propose that 1) the XLPP mutations destabilize the succinyl-CoA-induced hALAS2 closed conformation and thus accelerate ALA release, 2) the extended C-terminus of wild-type mammalian ALAS2 provides a regulatory role that allows for allosteric modulation of activity, thereby controlling the rate of erythroid heme biosynthesis, and 3) this control is disrupted in XLPP, resulting in porphyrin accumulation. PMID:26300302

  14. The screening of SLC6A8 deficiency among Estonian families with X-linked mental retardation.

    PubMed

    Puusepp, H; Kall, K; Salomons, G S; Talvik, I; Männamaa, M; Rein, R; Jakobs, C; Õunap, K

    2010-12-01

    The urinary creatine:creatinine (Cr:Crn) ratio was measured in males from 49 families with a family history compatible with X-linked mental retardation (XLMR) in order to estimate the prevalence of SLC6A8 deficiency in Estonia. We identified 11 boys from 9 families with an increased urinary Cr:Crn ratio (18%). In three related boys, a hemizygous missense mutation (c.1271G>A; p.Gly424Asp) was identified. Their mother was heterozygous for the same mutation. Although many missense mutations have been described, the p.Gly424Asp mutation has not been previously reported. The clinical expression varied widely among affected males of this family. Patients 1 and 3 had relatively mild clinical expression (mild mental retardation (MR) and attention deficit disorder), but patient 2 had all typical clinical signs of SLC6A8 defect such as moderate MR, autistic features, expressive dysphasia and epilepsy. Among our patients, we saw significant problems in speech and language development combined with attention and behavioural difficulties. The number of false-positive biochemical results with increased urinary Cr:Crn ratio was higher (18%) in our study than in previous reports (1.8–10%). We therefore suggest that repeated biochemical testing should be performed before DNA sequencing analysis. Our study suggests that 2% (95% confidence limits: 0.05–11.1%) of this Estonian XLMR panel are due to mutations in the SLC6A8, which is similar to the prevalence reported in other populations. We therefore conclude that creatine transporter deficiency is a relatively common genetic disorder in males with sporadic or familiar MR and diagnostic screening of them should always include screening for SLC6A8 deficiency. PMID:24137762

  15. X-Linked Hereditary Nephropathy in Navasota Dogs: Clinical Pathology, Morphology, and Gene Expression During Disease Progression.

    PubMed

    Benali, S L; Lees, G E; Nabity, M B; Aricò, A; Drigo, M; Gallo, E; Giantin, M; Aresu, L

    2016-07-01

    X-linked hereditary nephropathy (XLHN) in Navasota dogs is a spontaneously occurring disease caused by a mutation resulting in defective production of type IV collagen and juvenile-onset renal failure. The study was aimed at examining the evolution of renal damage and the expression of selected molecules potentially involved in the pathogenesis of XLHN. Clinical data and renal samples were obtained in 10 XLHN male dogs and 5 controls at 4 (T0), 6 (T1), and 9 (T2) months of age. Glomerular and tubulointerstitial lesions were scored by light microscopy, and the expression of 21 molecules was investigated by quantitative real-time polymerase chain reaction with selected proteins evaluated by immunohistochemistry. No significant histologic lesions or clinicopathologic abnormalities were identified in controls at any time-point. XLHN dogs had progressive proteinuria starting at T0. At T1, XLHN dogs had a mesangioproliferative glomerulopathy with glomerular loss, tubular necrosis, and interstitial fibrosis. At T2, glomerular and tubulointerstitial lesions were more severe, particularly glomerular loss, interstitial fibrosis, and inflammation. At T0, transforming growth factor β, connective tissue growth factor, and platelet-derived growth factor α mRNA were overexpressed in XLHN dogs compared with controls. Clusterin and TIMP1 transcripts were upregulated in later stages of the disease. Transforming growth factor β, connective tissue growth factor, and platelet-derived growth factor α should be considered as key players in the initial events of XHLN. Clusterin and TIMP1 appear to be more associated with the progression rather than initiation of tubulointerstitial damage in chronic renal disease. PMID:26917550

  16. Mineral uptake by the femora of older female X-linked hypophosphatemic (HYP) mice but not older male HYP mice.

    PubMed

    Brault, B A; Meyer, M H; Meyer, R A; Iorio, R J

    1987-09-01

    X-linked hypophosphatemic (Hyp) mice are a model of human sex-linked vitamin D-resistant rickets. Young adult Hyp mice are characterized by osteomalacia and decreased bone mineral content. However, older heterozygous Hyp female mice increase in bone mineral content with age so that by one year of age the bone mass/mm femoral length equals or exceeds normal females. To test for the occurrence of this mineral accretion in Hyp male mice and in homozygous Hyp female mice, femora from all 3 Hyp genotypes as well as normal male and female mice were analyzed at various ages from one to 52 weeks of age. Compared to normal mice, all three Hyp genotypes were depressed in bone ash, femoral length, and ash/length ratio at 13 weeks of age. After that age the femora of both heterozygous and homozygous Hyp females showed a slow mineral accretion and, by 52 weeks of age, a normal ash/length ratio. However, the femora of Hyp males, as well as those of normal males, failed to increase in bone mineral content or ash/length ratio after 13 weeks of age. The differences between male and female Hyp mice could not be explained by differences in the plasma levels of calcium, phosphate, or alkaline phosphatase. Increased bone mineral content in older Hyp mice was seen in both heterozygous and homozygous females but not in hemizygous males. Thus, the basis for this increase is not incomplete dominance of the Hyp gene in females nor the Lyon hypothesis. The accretion of mineral in older female Hyp mice despite lifelong reduced plasma phosphate levels suggests that there are factors other than phosphate that also regulate mineral accretion in this bone disease.

  17. Decreased N-TAF1 expression in X-linked dystonia-parkinsonism patient-specific neural stem cells

    PubMed Central

    Ito, Naoto; Hendriks, William T.; Dhakal, Jyotsna; Vaine, Christine A.; Liu, Christina; Shin, David; Shin, Kyle; Wakabayashi-Ito, Noriko; Dy, Marisela; Multhaupt-Buell, Trisha; Sharma, Nutan; Breakefield, Xandra O.; Bragg, D. Cristopher

    2016-01-01

    ABSTRACT X-linked dystonia-parkinsonism (XDP) is a hereditary neurodegenerative disorder involving a progressive loss of striatal medium spiny neurons. The mechanisms underlying neurodegeneration are not known, in part because there have been few cellular models available for studying the disease. The XDP haplotype consists of multiple sequence variations in a region of the X chromosome containing TAF1, a large gene with at least 38 exons, and a multiple transcript system (MTS) composed of five unconventional exons. A previous study identified an XDP-specific insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon in intron 32 of TAF1, as well as a neural-specific TAF1 isoform, N-TAF1, which showed decreased expression in post-mortem XDP brain compared with control tissue. Here, we generated XDP patient and control fibroblasts and induced pluripotent stem cells (iPSCs) in order to further probe cellular defects associated with this disease. As initial validation of the model, we compared expression of TAF1 and MTS transcripts in XDP versus control fibroblasts and iPSC-derived neural stem cells (NSCs). Compared with control cells, XDP fibroblasts exhibited decreased expression of TAF1 transcript fragments derived from exons 32-36, a region spanning the SVA insertion site. N-TAF1, which incorporates an alternative exon (exon 34′), was not expressed in fibroblasts, but was detectable in iPSC-differentiated NSCs at levels that were ∼threefold lower in XDP cells than in controls. These results support the previous findings that N-TAF1 expression is impaired in XDP, but additionally indicate that this aberrant transcription might occur in neural cells at relatively early stages of development that precede neurodegeneration. PMID:26769797

  18. Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium.

    PubMed

    de Brouwer, Arjan P M; Yntema, Helger G; Kleefstra, Tjitske; Lugtenberg, Dorien; Oudakker, Astrid R; de Vries, Bert B A; van Bokhoven, Hans; Van Esch, Hilde; Frints, Suzanne G M; Froyen, Guy; Fryns, Jean-Pierre; Raynaud, Martine; Moizard, Marie-Pierre; Ronce, Nathalie; Bensalem, Anissa; Moraine, Claude; Poirier, Karine; Castelnau, Laetitia; Saillour, Yoann; Bienvenu, Thierry; Beldjord, Chérif; des Portes, Vincent; Chelly, Jamel; Turner, Gillian; Fullston, Tod; Gecz, Jozef; Kuss, Andreas W; Tzschach, Andreas; Jensen, Lars Riff; Lenzner, Steffen; Kalscheuer, Vera M; Ropers, Hans-Hilger; Hamel, Ben C J

    2007-02-01

    The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers.

  19. Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.

    PubMed

    Naves, Luciana A; Daly, Adrian F; Dias, Luiz Augusto; Yuan, Bo; Zakir, Juliano Coelho Oliveira; Barra, Gustavo Barcellos; Palmeira, Leonor; Villa, Chiara; Trivellin, Giampaolo; Júnior, Armindo Jreige; Neto, Florêncio Figueiredo Cavalcante; Liu, Pengfei; Pellegata, Natalia S; Stratakis, Constantine A; Lupski, James R; Beckers, Albert

    2016-02-01

    X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome. PMID:26607152

  20. X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism is severely impaired in monocytes but not in lymphocytes

    PubMed Central

    Weber, Franziska D.; Wiesinger, Christoph; Forss-Petter, Sonja; Regelsberger, Günther; Einwich, Angelika; Weber, Willi H.A.; Köhler, Wolfgang; Stockinger, Hannes; Berger, Johannes

    2014-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the ABCD1 gene, encoding a member of the peroxisomal ABC transporter family. The ABCD1 protein transports CoA-activated very long-chain fatty acids (VLCFAs) into peroxisomes for degradation via β-oxidation. In the severest form, X-ALD patients suffer from inflammatory demyelination of the brain. As the extent of the metabolic defect in the main immune cells is unknown, we explored their phenotypes concerning mRNA expression pattern of the three peroxisomal ABC transporters, VLCFA accumulation and peroxisomal β-oxidation. In controls, ABCD1 expression was high in monocytes, intermediate in B cells and low in T cells; ABCD2 expression was extremely low in monocytes, intermediate in B cells and highest in T cells; ABCD3 mRNA was equally distributed. In X-ALD patients, the expression patterns remained unaltered; accordingly, monocytes, which lack compensatory VLCFA transport by ABCD2, displayed the severest biochemical phenotype with a 6-fold accumulation of C26:0 and a striking 70% reduction in peroxisomal β-oxidation activity. In contrast, VLCFA metabolism was close to control values in B cells and T cells, supporting the hypothesis that sufficient ABCD2 is present to compensate for ABCD1 deficiency. Thus, the vulnerability of the main immune cell types is highly variable in X-ALD. Based on these results, we propose that in X-ALD the halt of inflammation after allogeneic hematopoietic stem cell transplantation relies particularly on the replacement of the monocyte lineage. Additionally, these findings support the concept that ABCD2 is a target for pharmacological induction as an alternative therapeutic strategy. PMID:24363066

  1. A Korean boy with atypical X-linked adrenoleukodystrophy confirmed by an unpublished mutation of ABCD1

    PubMed Central

    Jwa, Hye Jeong; Lee, Keon Su; Kim, Gu Hwan; Yoo, Han Wook

    2014-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a rare peroxisomal disorder, that is rapidly progressive, neurodegenerative, and recessive, and characteristically primary affects the central nervous system white matter and the adrenal cortex. X-ALD is diagnosed basaed on clinical, radiological, and serological parameters, including elevated plasma levels of very long chain fatty acids (VLCFA), such as C24:0 and C26:0, and high C24:0/C22:0 and C26:0/C22:0 ratios. These tests are complemented with genetic analyses. A 7.5-year-old boy was admitted to Department of Pediatrics, Chungnam National University Hospital with progressive weakness of the bilateral lower extremities. Brain magnetic resonance imaging confirmed clinically suspected ALD. A low dose adrenocorticotropic hormone stimulation test revealed parital adrenal insufficiency. His fasting plasma levels of VLCFA showed that his C24:0/C22:0 and C26:0/C22:0 ratios were significantly elevated to 1.609 (normal, 0-1.390) and 0.075 (normal, 0-0.023), respectively. Genomic DNA was extracted from peripheral whole blood samples collected from the patient and his family. All exons of ABCD1 gene were amplified by polymerase chain reaction (PCR) using specific primers. Amplified PCR products were sequenced using the same primer pairs according to the manufacturer's instructions. We identified a missense mutation (p.Arg163Leu) in the ABCD1 gene of the proband caused by the nucleotide change 488G>T in exon 1. His asymptomatic mother carried the same mutation. We have reported an unpublished mutation in the ABCD1 gene in a patient with X-ALD, who showed increased ratio of C24:0/C22:0 and C26:0/C22:0, despite a normal VLCFA concentrations. PMID:25324868

  2. ABCD2 Is a Direct Target of β-Catenin and TCF-4: Implications for X-Linked Adrenoleukodystrophy Therapy

    PubMed Central

    Park, Chul-Yong; Kim, Han-Soo; Jang, Jiho; Lee, Hyunji; Lee, Jae Souk; Yoo, Jeong-Eun; Lee, Dongjin R.; Kim, Dong-Wook

    2013-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene that encodes the peroxisomal ATP-binding cassette (ABC) transporter subfamily D member 1 protein (ABCD1), which is referred to as the adrenoleukodystrophy protein (ALDP). Induction of the ABCD2 gene, the closest homolog of ABCD1, has been mentioned as a possible therapeutic option for the defective ABCD1 protein in X-ALD. However, little is known about the transcriptional regulation of ABCD2 gene expression. Here, through in silico analysis, we found two putative TCF-4 binding elements between nucleotide positions −360 and −260 of the promoter region of the ABCD2 gene. The transcriptional activity of the ABCD2 promoter was strongly increased by ectopic expression of β-catenin and TCF-4. In addition, mutation of either or both TCF-4 binding elements by site-directed mutagenesis decreased promoter activity. This was further validated by the finding that β-catenin and the promoter of the ABCD2 gene were pulled down with a β-catenin antibody in a chromatin immunoprecipitation assay. Moreover, real-time PCR analysis revealed that β-catenin and TCF-4 increased mRNA levels of ABCD2 in both a hepatocellular carcinoma cell line and primary fibroblasts from an X-ALD patient. Interestingly, we found that the levels of very long chain fatty acids were decreased by ectopic expression of ABCD2-GFP as well as β-catenin and TCF-4. Taken together, our results demonstrate for the first time the direct regulation of ABCD2 by β-catenin and TCF-4. PMID:23437103

  3. Zinc Finger and X-Linked Factor (ZFX) Binds to Human SET Transcript 2 Promoter and Transactivates SET Expression

    PubMed Central

    Xu, Siliang; Duan, Ping; Li, Jinping; Senkowski, Tristan; Guo, Fengbiao; Chen, Haibin; Romero, Alberto; Cui, Yugui; Liu, Jiayin; Jiang, Shi-Wen

    2016-01-01

    SET (SE Translocation) protein carries out multiple functions including those for protein phosphatase 2A (PP2A) inhibition, histone modification, DNA repair, and gene regulation. SET overexpression has been detected in brain neurons of patients suffering Alzheimer’s disease, follicle theca cells of Polycystic Ovary Syndrome (PCOS) patients, and ovarian cancer cells, indicating that SET may play a pathological role for these disorders. SET transcript 2, produced by a specific promoter, represents a major transcript variant in different cell types. In this study, we characterized the transcriptional activation of human SET transcript 2 promoter in HeLa cells. Promoter deletion experiments and co-transfection assays indicated that ZFX, the Zinc finger and X-linked transcription factor, was able to transactivate the SET promoter. A proximal promoter region containing four ZFX-binding sites was found to be critical for the ZFX-mediated transactivation. Mutagenesis study indicated that the ZFX-binding site located the closest to the transcription start site accounted for most of the ZFX-mediated transactivity. Manipulation of ZFX levels by overexpression or siRNA knockdown confirmed the significance and specificity of the ZFX-mediated SET promoter activation. Chromatin immunoprecipitation results verified the binding of ZFX to its cognate sites in the SET promoter. These findings have led to identification of ZFX as an upstream factor regulating SET gene expression. More studies are required to define the in vivo significance of this mechanism, and specifically, its implication for several benign and malignant diseases related to SET dysregulation. PMID:27775603

  4. Mapping of a possible X-linked form of familial developmental dysphasia (FDD) in a single large pedigree

    SciTech Connect

    Dunne, P.W.; Doody, R.S.; Epstein, H.F.

    1994-09-01

    Children diagnosed with developmental dysphasia develop speech very late without exhibiting sensory or motor dysfunction, and when they do begin to speak their grammar is abnormal. A large three-generation British pedigree was recently identified in which 16 out of 30 members were diagnosed as dysphasic. Assuming a dominant mode of inheritance with homogeneous phenotypic expression and complete penetrance among affected members, we showed by simulation analysis that this pedigree has the power to detect linkage to marker loci with an average maximum LOD score of 3.67 at {theta}=0.1. Given the absence of male-to-male transmission and a ratio of female to male affecteds (10/6) in this pedigree within the expected range for an X-linked dominant mode of inheritance, we decided to begin a genome-wide linkage analysis with microsatellite markers on the human X chromosome. Fifteen individuals (10 affected) from three generations were genotyped with 35 polymorphic STS`s (Research Genetics) which were approximately uniformly distributed along the X chromosome. Two-point linkage was assessed using the MLINK and ILINK programs from the LINKAGE package. Markers DXS1223, DXS987, DXS996 and DXS1060 on Xp22 showed consistent linkage to the disease locus with a maximum LOD score of 0.86 at a distance of 22 cM for DXS1060. If further analysis with additional markers and additional family members confirms X-linkage, such a localization would provide support for Lehrke`s hypothesis for X-linkage of major intellectual traits including verbal functioning.

  5. β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

    PubMed

    Hayflick, Susan J; Kruer, Michael C; Gregory, Allison; Haack, Tobias B; Kurian, Manju A; Houlden, Henry H; Anderson, James; Boddaert, Nathalie; Sanford, Lynn; Harik, Sami I; Dandu, Vasuki H; Nardocci, Nardo; Zorzi, Giovanna; Dunaway, Todd; Tarnopolsky, Mark; Skinner, Steven; Holden, Kenton R; Frucht, Steven; Hanspal, Era; Schrander-Stumpel, Connie; Mignot, Cyril; Héron, Delphine; Saunders, Dawn E; Kaminska, Margaret; Lin, Jean-Pierre; Lascelles, Karine; Cuno, Stephan M; Meyer, Esther; Garavaglia, Barbara; Bhatia, Kailash; de Silva, Rajith; Crisp, Sarah; Lunt, Peter; Carey, Martyn; Hardy, John; Meitinger, Thomas; Prokisch, Holger; Hogarth, Penelope

    2013-06-01

    Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

  6. Increased Sushi repeat-containing protein X-linked 2 is associated with progression of colorectal cancer.

    PubMed

    Liu, K L; Wu, J; Zhou, Y; Fan, J H

    2015-04-01

    Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel chondroitin sulfate proteoglycan overexpressed in gastrointestinal cancer. Its role in tumor biology remains unknown. The aim of this study was to investigate the expression of SRPX2 in colorectal cancer and its potential association with cancer progression. The expression of SRPX2 and its clinicopathological significance was evaluated using immunohistochemistry in a tissue microarray including 88 colon cancer and pairing normal tissues. The impact of SRPX2 on behavior of colorectal cancer cells and possible mechanism was explored using gene transfection and silencing. Strong staining of SRPX2 was noted in 71 (80.7 %) of 88 colon cancer specimen and 30 (34.1 %) of 88 adjacent normal tissues (P < 0.001). The expression of SRPX2 was significantly correlated with histological differentiation grade (P = 0.003), infiltration depth (P = 0.003), and clinical stage (P = 0.006). The expression of SRPX2 was significantly higher in HCT116 than in HT29 and SW480 cells. Suppression of endogenous SRPX2 expression by small interfering ribonucleic acid (siRNA) in HCT116 cells resulted in significant reduction in the ability of cell proliferation, adhesion, migration, and invasion. Up-regulation of endogenous SRPX2 in SW480 cells significantly promoted the migration and invasion of SW480 cells. In addition, inhibition of SRPX2 by siRNA led to notable down-regulation of β-catenin, matrix metalloproteinase (MMP)-2, and MMP-9. These findings indicate that overexpressed SRPX2 exerts an oncogenic role in colorectal cancer. SRPX2 may promote the invasion of colorectal cancer through MMP-2 and MMP-9 modulated by Wnt/β-catenin pathway.

  7. A recombination outside the BB deletion refines the location of the X-linked retinitis pigmentosa locus RP3

    SciTech Connect

    Fujita, R.; Bingham, E.; Forsythe, P.; McHenry, C.

    1996-07-01

    Genetic loci for X-linked retinitis pigmentosa (XLRP) have been mapped between Xp11.22 and Xp22.13 (RP2, RP3, RP6, and RP15). The RP3 gene, which is responsible for the predominant form of XLRP in most Caucasian populations, has been localized to Xp21.1 by linkage analysis and the map positions of chromosomal deletions associated with the disease. Previous linkage studies have suggested that RP3 is flanked by the markers DXS1110 (distal) and OTC (proximal). Patient BB was though to have RP because of a lesion at the RP3 locus, in addition to chronic granulomatous disease, Duchenne muscular dystrophy (DMD), mild mental retardation, and the McLeod phenotype. This patient carried a deletion extending {approximately}3 Mb from DMD in Xp21.3 to Xp21.1, with the proximal breakpoint located {approximately}40 kb centromeric to DXS1110. The RP3 gene, therefore, is believed to reside between DXS1110 and the proximal breakpoint of the BB deletion. In order to refine the location of RP3 and to ascertain patients with RP3, we have been analyzing several XLRP families for linkage to Xp markers. Linkage analysis in an American family of 27 individuals demonstrates segregation of XLRP with markers in Xp21.1, consistent with the RP3 subtype. One affected male shows a recombination event proximal to DXS1110. Additional markers within the DXS1110-OTC interval show that the crossover is between two novel polymorphic markers, DXS8349 and M6, both of which are present in BB DNA and lie centromeric to the proximal breakpoint. This recombination places the XLRP mutation in this family outside the BB deletion and redefines the location of RP3. 22 refs., 3 figs., 2 tabs.

  8. Increased Sushi repeat-containing protein X-linked 2 is associated with progression of colorectal cancer.

    PubMed

    Liu, K L; Wu, J; Zhou, Y; Fan, J H

    2015-04-01

    Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel chondroitin sulfate proteoglycan overexpressed in gastrointestinal cancer. Its role in tumor biology remains unknown. The aim of this study was to investigate the expression of SRPX2 in colorectal cancer and its potential association with cancer progression. The expression of SRPX2 and its clinicopathological significance was evaluated using immunohistochemistry in a tissue microarray including 88 colon cancer and pairing normal tissues. The impact of SRPX2 on behavior of colorectal cancer cells and possible mechanism was explored using gene transfection and silencing. Strong staining of SRPX2 was noted in 71 (80.7 %) of 88 colon cancer specimen and 30 (34.1 %) of 88 adjacent normal tissues (P < 0.001). The expression of SRPX2 was significantly correlated with histological differentiation grade (P = 0.003), infiltration depth (P = 0.003), and clinical stage (P = 0.006). The expression of SRPX2 was significantly higher in HCT116 than in HT29 and SW480 cells. Suppression of endogenous SRPX2 expression by small interfering ribonucleic acid (siRNA) in HCT116 cells resulted in significant reduction in the ability of cell proliferation, adhesion, migration, and invasion. Up-regulation of endogenous SRPX2 in SW480 cells significantly promoted the migration and invasion of SW480 cells. In addition, inhibition of SRPX2 by siRNA led to notable down-regulation of β-catenin, matrix metalloproteinase (MMP)-2, and MMP-9. These findings indicate that overexpressed SRPX2 exerts an oncogenic role in colorectal cancer. SRPX2 may promote the invasion of colorectal cancer through MMP-2 and MMP-9 modulated by Wnt/β-catenin pathway. PMID:25737434

  9. X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity

    PubMed Central

    Evans, M K; Sauer, S J; Nath, S; Robinson, T J; Morse, M A; Devi, G R

    2016-01-01

    Inflammatory breast cancer (IBC) is the deadliest, distinct subtype of breast cancer. High expression of epidermal growth factor receptors [EGFR or human epidermal growth factor receptor 2 (HER2)] in IBC tumors has prompted trials of anti-EGFR/HER2 monoclonal antibodies to inhibit oncogenic signaling; however, de novo and acquired therapeutic resistance is common. Another critical function of these antibodies is to mediate antibody-dependent cellular cytotoxicity (ADCC), which enables immune effector cells to engage tumors and deliver granzymes, activating executioner caspases. We hypothesized that high expression of anti-apoptotic molecules in tumors would render them resistant to ADCC. Herein, we demonstrate that the most potent caspase inhibitor, X-linked inhibitor of apoptosis protein (XIAP), overexpressed in IBC, drives resistance to ADCC mediated by cetuximab (anti-EGFR) and trastuzumab (anti-HER2). Overexpression of XIAP in parental IBC cell lines enhances resistance to ADCC; conversely, targeted downregulation of XIAP in ADCC-resistant IBC cells renders them sensitive. As hypothesized, this ADCC resistance is in part a result of the ability of XIAP to inhibit caspase activity; however, we also unexpectedly found that resistance was dependent on XIAP-mediated, caspase-independent suppression of reactive oxygen species (ROS) accumulation, which otherwise occurs during ADCC. Transcriptome analysis supported these observations by revealing modulation of genes involved in immunosuppression and oxidative stress response in XIAP-overexpressing, ADCC-resistant cells. We conclude that XIAP is a critical modulator of ADCC responsiveness, operating through both caspase-dependent and -independent mechanisms. These results suggest that strategies targeting the effects of XIAP on caspase activation and ROS suppression have the potential to enhance the activity of monoclonal antibody-based immunotherapy. PMID:26821068

  10. Identification and Glycerol-Induced Correction of Misfolding Mutations in the X-Linked Mental Retardation Gene CASK

    PubMed Central

    LaConte, Leslie E. W.; Chavan, Vrushali; Mukherjee, Konark

    2014-01-01

    The overwhelming amount of available genomic sequence variation information demands a streamlined approach to examine known pathogenic mutations of any given protein. Here we seek to outline a strategy to easily classify pathogenic missense mutations that cause protein misfolding and are thus good candidates for chaperone-based therapeutic strategies, using previously identified mutations in the gene CASK. We applied a battery of bioinformatics algorithms designed to predict potential impact on protein structure to five pathogenic missense mutations in the protein CASK that have been shown to underlie pathologies ranging from X-linked mental retardation to autism spectrum disorder. A successful classification of the mutations as damaging was not consistently achieved despite the known pathogenicity. In addition to the bioinformatics analyses, we performed molecular modeling and phylogenetic comparisons. Finally, we developed a simple high-throughput imaging assay to measure the misfolding propensity of the CASK mutants in situ. Our data suggests that a phylogenetic analysis may be a robust method for predicting structurally damaging mutations in CASK. Mutations in two evolutionarily invariant residues (Y728C and W919R) exhibited a strong propensity to misfold and form visible aggregates in the cytosolic milieu. The remaining mutations (R28L, Y268H, and P396S) showed no evidence of aggregation and maintained their interactions with known CASK binding partners liprin-α3 Mint-1, and Veli, indicating an intact structure. Intriguingly, the protein aggregation caused by the Y728C and W919R mutations was reversed by treating the cells with a chemical chaperone (glycerol), providing a possible therapeutic strategy for treating structural mutations in CASK in the future. PMID:24505460

  11. Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK.

    PubMed

    LaConte, Leslie E W; Chavan, Vrushali; Mukherjee, Konark

    2014-01-01

    The overwhelming amount of available genomic sequence variation information demands a streamlined approach to examine known pathogenic mutations of any given protein. Here we seek to outline a strategy to easily classify pathogenic missense mutations that cause protein misfolding and are thus good candidates for chaperone-based therapeutic strategies, using previously identified mutations in the gene CASK. We applied a battery of bioinformatics algorithms designed to predict potential impact on protein structure to five pathogenic missense mutations in the protein CASK that have been shown to underlie pathologies ranging from X-linked mental retardation to autism spectrum disorder. A successful classification of the mutations as damaging was not consistently achieved despite the known pathogenicity. In addition to the bioinformatics analyses, we performed molecular modeling and phylogenetic comparisons. Finally, we developed a simple high-throughput imaging assay to measure the misfolding propensity of the CASK mutants in situ. Our data suggests that a phylogenetic analysis may be a robust method for predicting structurally damaging mutations in CASK. Mutations in two evolutionarily invariant residues (Y728C and W919R) exhibited a strong propensity to misfold and form visible aggregates in the cytosolic milieu. The remaining mutations (R28L, Y268H, and P396S) showed no evidence of aggregation and maintained their interactions with known CASK binding partners liprin-α3 Mint-1, and Veli, indicating an intact structure. Intriguingly, the protein aggregation caused by the Y728C and W919R mutations was reversed by treating the cells with a chemical chaperone (glycerol), providing a possible therapeutic strategy for treating structural mutations in CASK in the future.

  12. Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.

    PubMed

    Naves, Luciana A; Daly, Adrian F; Dias, Luiz Augusto; Yuan, Bo; Zakir, Juliano Coelho Oliveira; Barra, Gustavo Barcellos; Palmeira, Leonor; Villa, Chiara; Trivellin, Giampaolo; Júnior, Armindo Jreige; Neto, Florêncio Figueiredo Cavalcante; Liu, Pengfei; Pellegata, Natalia S; Stratakis, Constantine A; Lupski, James R; Beckers, Albert

    2016-02-01

    X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

  13. Genetics of Human and Canine Dilated Cardiomyopathy

    PubMed Central

    Simpson, Siobhan; Edwards, Jennifer; Ferguson-Mignan, Thomas F. N.; Cobb, Malcolm; Mongan, Nigel P.; Rutland, Catrin S.

    2015-01-01

    Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed. PMID:26266250

  14. Interdisciplinary approach to palatally impacted canine

    PubMed Central

    Goel, Ashish; Loomba, Anju; Goel, Poonam; Sharma, Naresh

    2010-01-01

    Interdisciplinary approach for the management of malocclusion provides a holistic approach of patient management. Prudent treatment planning is necessary to achieve the various treatment goals. The article highlights the salient features and various surgical and orthodontic considerations to approach cases with impacted canines. It is exemplified with a case in which a palatally impacted canine and a highly placed canine in the buccal vestibule have been surgically intervened and orthodontically extruded with sequential traction and aligned in the arch. PMID:22442552

  15. Canine histiocytic neoplasia: An overview

    PubMed Central

    Fulmer, Amanda K.; Mauldin, Glenna E.

    2007-01-01

    Canine histiocytic neoplasms include cutaneous histiocytoma, as well as localized and disseminated histiocytic sarcoma. These tumors have variable biologic behavior, although the malignant disorders often have a poor prognosis. Immunohistochemistry plays an essential role in differentiating histiocytic tumors from other neoplasias that may have similar histological appearances. This allows a definitive diagnosis to be established and provides a more accurate prediction of prognosis. This article reviews the biologic behavior, diagnosis, and treatment of histiocytic tumors in the dog. PMID:17987966

  16. Canine Blastomycosis in Southern Saskatchewan

    PubMed Central

    Harasen, Greg L.G.; Randall, James W.

    1986-01-01

    The incidence of canine blastomycosis in southern Saskatchewan is examined and three clinical cases are described. Nineteen cases of the disease have been diagnosed in southern Saskatchewan since April of 1981. Eight cases were diagnosed during a six month period from August 1985 to February 1986 in dogs residing in a small central area of Regina. The geographical and chronological clustering of cases suggests a local source of exposure to Blastomyces dermatitidis, not previously considered to be endemic to Saskatchewan. PMID:17422705

  17. Sewage surveillance reveals the presence of canine GVII norovirus and canine astrovirus in Uruguay.

    PubMed

    Lizasoain, A; Tort, L F L; García, M; Gómez, M M; Leite, J P G; Miagostovich, M P; Cristina, J; Berois, M; Colina, R; Victoria, Matías

    2015-11-01

    Canine norovirus (NoV) and astrovirus (AstV) were studied in 20 domestic sewage samples collected in two cities in Uruguay. Four samples were characterized as canine AstV after phylogenetic analysis clustering with strains detected in Italy and Brazil in 2008 and 2012, respectively. One sample was characterized as canine NoV and clustered with a strain detected in Hong Kong and recently classified as GVII. This study shows the occurrence of a canine NoV GVII strain for the first time in the American continent and also warns about possible zoonotic infection, since canine strains were detected in domestic sewage.

  18. Genome Sequence of Canine Herpesvirus

    PubMed Central

    Papageorgiou, Konstantinos V.; Suárez, Nicolás M.; Wilkie, Gavin S.; McDonald, Michael; Graham, Elizabeth M.; Davison, Andrew J.

    2016-01-01

    Canine herpesvirus is a widespread alphaherpesvirus that causes a fatal haemorrhagic disease of neonatal puppies. We have used high-throughput methods to determine the genome sequences of three viral strains (0194, V777 and V1154) isolated in the United Kingdom between 1985 and 2000. The sequences are very closely related to each other. The canine herpesvirus genome is estimated to be 125 kbp in size and consists of a unique long sequence (97.5 kbp) and a unique short sequence (7.7 kbp) that are each flanked by terminal and internal inverted repeats (38 bp and 10.0 kbp, respectively). The overall nucleotide composition is 31.6% G+C, which is the lowest among the completely sequenced alphaherpesviruses. The genome contains 76 open reading frames predicted to encode functional proteins, all of which have counterparts in other alphaherpesviruses. The availability of the sequences will facilitate future research on the diagnosis and treatment of canine herpesvirus-associated disease. PMID:27213534

  19. Behavioural and Psychiatric Phenotypes in Men and Boys with X-Linked Ichthyosis: Evidence from a Worldwide Online Survey

    PubMed Central

    Chatterjee, Sohini; Humby, Trevor; Davies, William

    2016-01-01

    Background X-linked ichthyosis (XLI) is a rare dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). Preliminary evidence in boys with XLI, and animal model studies, suggests that individuals lacking STS are at increased risk of developmental disorders and associated traits. However, the behavioural profile of children with XLI is poorly-characterised, and the behavioural profile of adults with XLI has not yet been documented at all. Materials and Methods Using an online survey, advertised worldwide, we collected detailed self- or parent-reported information on behaviour in adult (n = 58) and younger (≤18yrs, n = 24) males with XLI for comparison to data from their non-affected brothers, and age/gender-matched previously-published normative data. The survey comprised demographic and background information (including any prior clinical diagnoses) and validated questionnaires assaying phenotypes of particular interest (Adult ADHD Self-Report Scale v1.1, Barrett Impulsiveness Scale-11, adult and adolescent Autism Quotient, Kessler Psychological Distress Scales, and Disruptive Behaviour Disorder Rating Scale). Results Individuals with XLI generally exhibited normal sensory function. Boys with XLI were at increased risk of developmental disorder, whilst adults with the condition were at increased risk of both developmental and mood disorders. Both adult and younger XLI groups scored significantly more highly than male general population norms on measures of inattention, impulsivity, autism-related traits, psychological distress and disruptive behavioural traits. Conclusions These findings indicate that both adult and younger males with XLI exhibit personality profiles that are distinct from those of males within the general population, and suggest that individuals with XLI may be at heightened risk of psychopathology. The data are consistent with the notion that STS is important in neurodevelopment and ongoing brain function, and

  20. Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23

    PubMed Central

    Zhang, Xiaoping; Ruppe, Mary D.; Weber, Thomas J.; Klausner, Mark A.; Ito, Takahiro; Vergeire, Maria; Humphrey, Jeffrey S.; Glorieux, Francis H.; Portale, Anthony A.; Insogna, Karl; Peacock, Munro; Carpenter, Thomas O.

    2015-01-01

    Context: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. Objective: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. Design: Two sequential open-label phase 1/2 studies were done. Setting: Six academic medical centers were used. Participants: Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05–0.6 mg/kg); 22 entered a 12-month extension study (0.1–1 mg/kg). Intervention: KRN23 was injected sc every 28 days. Main Outcome Measure: The main outcome measure was the proportion of subjects attaining normal serum Pi and safety. Results: At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3–7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9–85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile. Conclusions: Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH. PMID:25919461

  1. Cord Blood Stem Cell-Mediated Induction of Apoptosis in Glioma Downregulates X-Linked Inhibitor of Apoptosis Protein (XIAP)

    PubMed Central

    Dasari, Venkata Ramesh; Velpula, Kiran Kumar; Kaur, Kiranpreet; Fassett, Daniel; Klopfenstein, Jeffrey D.; Dinh, Dzung H.; Gujrati, Meena; Rao, Jasti S.

    2010-01-01

    Background XIAP (X-linked inhibitor of apoptosis protein) is one of the most important members of the apoptosis inhibitor family. XIAP is upregulated in various malignancies, including human glioblastoma. It promotes invasion, metastasis, growth and survival of malignant cells. We hypothesized that downregulation of XIAP by human umbilical cord blood mesenchymal stem cells (hUCBSC) in glioma cells would cause them to undergo apoptotic death. Methodology/Principal Findings We observed the effect of hUCBSC on two malignant glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310). In co-cultures of glioma cells with hUCBSC, proliferation of glioma cells was significantly inhibited. This is associated with increased cytotoxicity of glioma cells, which led to glioma cell death. Stem cells induced apoptosis in glioma cells, which was evaluated by TUNEL assay, FACS analyses and immunoblotting. The induction of apoptosis is associated with inhibition of XIAP in co-cultures of hUCBSC. Similar results were obtained by the treatment of glioma cells with shRNA to downregulate XIAP (siXIAP). Downregulation of XIAP resulted in activation of caspase-3 and caspase-9 to trigger apoptosis in glioma cells. Apoptosis is characterized by the loss of mitochondrial membrane potential and upregulation of mitochondrial apoptotic proteins Bax and Bad. Cell death of glioma cells was marked by downregulation of Akt and phospho-Akt molecules. We observed similar results under in vivo conditions in U251- and 5310-injected nude mice brains, which were treated with hUCBSC. Under in vivo conditions, Smac/DIABLO was found to be colocalized in the nucleus, showing that hUCBSC induced apoptosis is mediated by inhibition of XIAP and activation of Smac/DIABLO. Conclusions/Significance Our results indicate that downregulation of XIAP by hUCBSC treatment induces apoptosis, which led to the death of the glioma cells and xenograft cells. This study demonstrates the therapeutic

  2. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.

    PubMed

    Iacovazzo, Donato; Caswell, Richard; Bunce, Benjamin; Jose, Sian; Yuan, Bo; Hernández-Ramírez, Laura C; Kapur, Sonal; Caimari, Francisca; Evanson, Jane; Ferraù, Francesco; Dang, Mary N; Gabrovska, Plamena; Larkin, Sarah J; Ansorge, Olaf; Rodd, Celia; Vance, Mary L; Ramírez-Renteria, Claudia; Mercado, Moisés; Goldstone, Anthony P; Buchfelder, Michael; Burren, Christine P; Gurlek, Alper; Dutta, Pinaki; Choong, Catherine S; Cheetham, Timothy; Trivellin, Giampaolo; Stratakis, Constantine A; Lopes, Maria-Beatriz; Grossman, Ashley B; Trouillas, Jacqueline; Lupski, James R; Ellard, Sian; Sampson, Julian R; Roncaroli, Federico; Korbonits, Márta

    2016-01-01

    Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101

  3. A yeast artificial chromosome (YAC) contig encompassing the critical region of the X-linked lymphoproliferative disease (XLP) locus.

    PubMed

    Lanyi, A; Li, B; Li, S; Talmadge, C B; Brichacek, B; Davis, J R; Kozel, B A; Trask, B; van den Engh, G; Uzvolgyi, E; Stanbridge, E J; Nelson, D L; Chinault, C; Heslop, H; Gross, T G; Seemayer, T A; Klein, G; Purtilo, D T; Sumegi, J

    1997-01-01

    X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability to Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia, or malignant lymphoma. Initially the XLP gene was assigned to a 10-cM region in Xq25 between DXS42 and DXS37. Subsequently, an interstitial, cytogenetically visible deletion in Xq25 was identified in one XLP family, 43. In this study we estimated the deletion in XLP patient 43-004 by dual-laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mb of DNA sequence. From a human chromosome Xq25-specific yeast artificial chromosome (YAC) sublibrary, five YACs containing DNA sequences deleted in patient 43-004 have been isolated. Sequence-tagged sites (STSs) from these YACs have been used to identify interstitial deletions in unrelated XLP patients. Three more families with interstitial deletions were found. Two of the patients (63-003 and 73-032) carried an interstitial deletion of 3.0 Mb overlapping the 43-004 deletion. In one XLP patient (30-011) who exhibited the characteristic postinfectious mononucleosis phenotype of XLP with hypogammaglobulinemia and malignant lymphoma, a deletion of approximately 250 kb was detected overlapping the deletion detected in patients 43-004, 63-003, and 73-032. A YAC contig of 2.2 Mb spanning the XLP critical region, whose orientation on chromosome X was determined by double-color fluorescence in situ hybridization and which consists of 15 overlapping YAC clones, has been constructed. A detailed restriction enzyme map of the region has been constructed. YAC insert sizes were determined by counter-clamped homogenous electric field gel electrophoresis. Chimerism of YACs was determined by FISH and restriction mapping. On the basis of lambda subclones, YAC end-derived plasmids, and STSs with an average spacing of 100 kb, a long-range physical map was constructed using 5 rare-cutter restriction

  4. Novel X-linked syndrome of cardiac valvulopathy, keloid scarring, and reduced joint mobility due to filamin A substitution G1576R.

    PubMed

    Atwal, Paldeep Singh; Blease, Sophie; Braxton, Alicia; Graves, Julia; He, Weimin; Person, Richard; Slattery, Leah; Bernstein, Jonathan Adam; Hudgins, Louanne

    2016-04-01

    Filamin A (FLNA) is known to be involved in intracellular actin binding, cell migration, scaffolding, and signaling. We report a novel X-linked syndrome characterized by cardiac valvular disease, keloid scarring and reduced joint mobility in male second cousins due to a previously unreported mutation in FLNA. Whole exome sequencing was performed using standard methods and segregation analysis was performed in affected and non-affected family members. A novel hemizygous c.4726G>A (p.G1576R) mutation in FLNA was detected. Segregation analysis performed on multiple maternal family members showed c.4726G>A (p.G1576R) segregated with disease in an X-linked inheritance pattern. The findings in these cases are distinct from previously described FLNA related disorders by virtue of decreased joint mobility and spontaneous keloid scarring. They occur in association with a novel mutation and represent a novel genetic syndrome.

  5. X-linked mental retardation with neonatal hypotonia in a French family (MRX15): Gene assignment to Xp11.22-Xp21.1

    SciTech Connect

    Raynaud, M.; Dessay, B.; Ayrault, A.D.

    1996-07-12

    Linkage analysis was performed in a family with non-specific X-linked mental retardation (MRX 15). Hypotonia in infancy was the most remarkable physical manifestation. The severity of mental deficiency was variable among the patients, but all of them had poor or absent speech. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS1126, DXS255, and DXS573 (Zmax = 2.01) and recombination was observed with the two flanking loci DXS164 (Xp21.1) and DXS988 (Xp11.22), identifying a 17 cM interval. This result suggests a new gene localization in the proximal Xp region. In numerous families with non-specific X-linked mental retardation (MRX), the corresponding gene has been localized to the paracentromeric region in which a low recombination rate impairs the precision of mapping. 58 refs., 3 figs., 5 tabs.

  6. Vertebral Osteomyelitis and Acinetobacter Spp. Paravertebral Soft Tissue Infection in a 4-Year-Old Boy With X-Linked Chronic Granulomatous Disease.

    PubMed

    Vignesh, Pandiarajan; Bhattad, Sagar; Shandilya, Jitendra-Kumar; Vyas, Sameer; Garg, Rashi; Rawat, Amit

    2016-09-01

    Vertebral osteomyelitis is known to occur in chronic granulomatous disease, a phagocytic disorder and the etiology is usually a fungus. Indolent spread of fungal infection from lungs to adjacent ribs and vertebra often results in persistent pneumonia and vertebral deformities. We report a 4-year-old boy with chronic cough and kyphosis, who had a fungal vertebral osteomyelitis and Acinetobacter spp. paravertebral soft tissue infection related to X-linked chronic granulomatous disease.

  7. Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6.

    PubMed

    Rost, Simone; Bach, Elisa; Neuner, Cordula; Nanda, Indrajit; Dysek, Sandra; Bittner, Reginald E; Keller, Alexander; Bartsch, Oliver; Mlynski, Robert; Haaf, Thomas; Müller, Clemens R; Kunstmann, Erdmute

    2014-02-01

    Hereditary hearing loss is the most common human sensorineural disorder. Genetic causes are highly heterogeneous, with mutations detected in >40 genes associated with nonsyndromic hearing loss, to date. Whereas autosomal recessive and autosomal dominant inheritance is prevalent, X-linked forms of nonsyndromic hearing impairment are extremely rare. Here, we present a Hungarian three-generation family with X-linked nonsyndromic congenital hearing loss and the underlying genetic defect. Next-generation sequencing and subsequent segregation analysis detected a missense mutation (c.1771G>A, p.Gly591Ser) in the type IV collagen gene COL4A6 in all affected family members. Bioinformatic analysis and expression studies support this substitution as being causative. COL4A6 encodes the alpha-6 chain of type IV collagen of basal membranes, which forms a heterotrimer with two alpha-5 chains encoded by COL4A5. Whereas mutations in COL4A5 and contiguous X-chromosomal deletions involving COL4A5 and COL4A6 are associated with X-linked Alport syndrome, a nephropathy associated with deafness and cataract, mutations in COL4A6 alone have not been related to any hereditary disease so far. Moreover, our index patient and other affected family members show normal renal and ocular function, which is not consistent with Alport syndrome, but with a nonsyndromic type of hearing loss. In situ hybridization and immunostaining demonstrated expression of the COL4A6 homologs in the otic vesicle of the zebrafish and in the murine inner ear, supporting its role in normal ear development and function. In conclusion, our results suggest COL4A6 as being the fourth gene associated with X-linked nonsyndromic hearing loss. PMID:23714752

  8. Comparative Analysis of Protocadherin-11 X-Linked Expression among Postnatal Rodents, Non-Human Primates, and Songbirds Suggests Its Possible Involvement in Brain Evolution

    PubMed Central

    Matsunaga, Eiji; Nambu, Sanae; Oka, Mariko; Okanoya, Kazuo; Iriki, Atsushi

    2013-01-01

    Background Protocadherin-11 is a cell adhesion molecule of the cadherin superfamily. Since, only in humans, its paralog is found on the Y chromosome, it is expected that protocadherin-11X/Y plays some role in human brain evolution or sex differences. Recently, a genetic mutation of protocadherin-11X/Y was reported to be associated with a language development disorder. Here, we compared the expression of protocadherin-11 X-linked in developing postnatal brains of mouse (rodent) and common marmoset (non-human primate) to explore its possible involvement in mammalian brain evolution. We also investigated its expression in the Bengalese finch (songbird) to explore a possible function in animal vocalization and human language faculties. Methodology/Principal Findings Protocadherin-11 X-linked was strongly expressed in the cerebral cortex, hippocampus, amygdala and brainstem. Comparative analysis between mice and marmosets revealed that in certain areas of marmoset brain, the expression was clearly enriched. In Bengalese finches, protocadherin-11 X-linked was expressed not only in nuclei of regions of the vocal production pathway and the tracheosyringeal hypoglossal nucleus, but also in areas homologous to the mammalian amygdala and hippocampus. In both marmosets and Bengalese finches, its expression in pallial vocal control areas was developmentally regulated, and no clear expression was seen in the dorsal striatum, indicating a similarity between songbirds and non-human primates. Conclusions/Significance Our results suggest that the enriched expression of protocadherin-11 X-linked is involved in primate brain evolution and that some similarity exists between songbirds and primates regarding the neural basis for vocalization. PMID:23527036

  9. Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6.

    PubMed

    Rost, Simone; Bach, Elisa; Neuner, Cordula; Nanda, Indrajit; Dysek, Sandra; Bittner, Reginald E; Keller, Alexander; Bartsch, Oliver; Mlynski, Robert; Haaf, Thomas; Müller, Clemens R; Kunstmann, Erdmute

    2014-02-01

    Hereditary hearing loss is the most common human sensorineural disorder. Genetic causes are highly heterogeneous, with mutations detected in >40 genes associated with nonsyndromic hearing loss, to date. Whereas autosomal recessive and autosomal dominant inheritance is prevalent, X-linked forms of nonsyndromic hearing impairment are extremely rare. Here, we present a Hungarian three-generation family with X-linked nonsyndromic congenital hearing loss and the underlying genetic defect. Next-generation sequencing and subsequent segregation analysis detected a missense mutation (c.1771G>A, p.Gly591Ser) in the type IV collagen gene COL4A6 in all affected family members. Bioinformatic analysis and expression studies support this substitution as being causative. COL4A6 encodes the alpha-6 chain of type IV collagen of basal membranes, which forms a heterotrimer with two alpha-5 chains encoded by COL4A5. Whereas mutations in COL4A5 and contiguous X-chromosomal deletions involving COL4A5 and COL4A6 are associated with X-linked Alport syndrome, a nephropathy associated with deafness and cataract, mutations in COL4A6 alone have not been related to any hereditary disease so far. Moreover, our index patient and other affected family members show normal renal and ocular function, which is not consistent with Alport syndrome, but with a nonsyndromic type of hearing loss. In situ hybridization and immunostaining demonstrated expression of the COL4A6 homologs in the otic vesicle of the zebrafish and in the murine inner ear, supporting its role in normal ear development and function. In conclusion, our results suggest COL4A6 as being the fourth gene associated with X-linked nonsyndromic hearing loss.

  10. X-linked Alport syndrome: An SSCP-based mutation survey over all 51 exons of the COL4A5 gene

    SciTech Connect

    Renieri, A.; Bruttini, M.; Galli, L.; Ballabio, A.; De Marchi, M.

    1996-06-01

    The COL4A5 gene encodes the {alpha}5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the {alpha}5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients. 44 refs., 3 figs., 4 tabs.

  11. Two unique mutations in the interleukin-2 receptor gamma chain gene (IL2RG) cause X-linked severe combined immunodeficiency arising in opposite parental germ lines

    SciTech Connect

    Puck, J.M.; Pepper, A.E.

    1994-09-01

    The gene encoding the gamma chain of the lymphocyte receptor for IL-2 lies in human X13.1 and is mutated in males with X-linked severe combined immunodeficiency (SCID). 27 X-linked SCID mutations have been found in our laboratory. Single strand conformation polymorphism (SSCP) analysis of genomic DNA using primers flanking each of the 8 exons was followed by direct sequencing of abnormally migrating fragments from SCID patients and family members. A 9 bp in-frame duplication insertion was found in IL2RG exon 5 of a patient from a large X-linked SCID pedigree; the resulting duplication of 3 extracellular amino acids, including the first tryptophan of the {open_quotes}WSXWS{close_quotes} cytokine binding motif, is predicted to disrupt interaction of the cytokine receptor chain with its ligand. Genetic linkage studies demonstrated that the grandmaternal X chromosome associated with SCID was contributed to 3 daughters, 2 obligate carriers and 1 woman of unknown status. However, this grandmother`s genomic DNA did not contain the insertion mutation, nor did she have skewed X-chromosome inactivation in her lymphocytes. That both obligate carrier daughters, but not the third daughter, had the insertion proved the grandmother to be a germline mosaic. A second proband had X-linked SCID with a branch point mutation due to substitution of T for A 15 bp 5{prime} of the start of IL2RG exon 3. This mutation resulted in undetectable IL2RG mRNA by Northern blot. Linkage analysis and sequencing of IL2RG DNA in this family proved the mutation to have originated in the germline of the proband`s grandfather, an immunocompetent individual who contributed an X chromosome with normal IL2RG to one daughter and a mutated X to the another.

  12. Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6

    PubMed Central

    Rost, Simone; Bach, Elisa; Neuner, Cordula; Nanda, Indrajit; Dysek, Sandra; Bittner, Reginald E; Keller, Alexander; Bartsch, Oliver; Mlynski, Robert; Haaf, Thomas; Müller, Clemens R; Kunstmann, Erdmute

    2014-01-01

    Hereditary hearing loss is the most common human sensorineural disorder. Genetic causes are highly heterogeneous, with mutations detected in >40 genes associated with nonsyndromic hearing loss, to date. Whereas autosomal recessive and autosomal dominant inheritance is prevalent, X-linked forms of nonsyndromic hearing impairment are extremely rare. Here, we present a Hungarian three-generation family with X-linked nonsyndromic congenital hearing loss and the underlying genetic defect. Next-generation sequencing and subsequent segregation analysis detected a missense mutation (c.1771G>A, p.Gly591Ser) in the type IV collagen gene COL4A6 in all affected family members. Bioinformatic analysis and expression studies support this substitution as being causative. COL4A6 encodes the alpha-6 chain of type IV collagen of basal membranes, which forms a heterotrimer with two alpha-5 chains encoded by COL4A5. Whereas mutations in COL4A5 and contiguous X-chromosomal deletions involving COL4A5 and COL4A6 are associated with X-linked Alport syndrome, a nephropathy associated with deafness and cataract, mutations in COL4A6 alone have not been related to any hereditary disease so far. Moreover, our index patient and other affected family members show normal renal and ocular function, which is not consistent with Alport syndrome, but with a nonsyndromic type of hearing loss. In situ hybridization and immunostaining demonstrated expression of the COL4A6 homologs in the otic vesicle of the zebrafish and in the murine inner ear, supporting its role in normal ear development and function. In conclusion, our results suggest COL4A6 as being the fourth gene associated with X-linked nonsyndromic hearing loss. PMID:23714752

  13. X-linked Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene.

    PubMed Central

    Renieri, A.; Bruttini, M.; Galli, L.; Zanelli, P.; Neri, T.; Rossetti, S.; Turco, A.; Heiskari, N.; Zhou, J.; Gusmano, R.; Massella, L.; Banfi, G.; Scolari, F.; Sessa, A.; Rizzoni, G.; Tryggvason, K.; Pignatti, P. F.; Savi, M.; Ballabio, A.; De Marchi, M.

    1996-01-01

    The COL4A5 gene encodes the alpha5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 start codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the alpha5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients. PMID:8651296

  14. A novel mutation in FHL1 in a family with X-linked scapuloperoneal myopathy: phenotypic spectrum and structural study of FHL1 mutations

    PubMed Central

    Chen, Dong-Hui; Raskind, Wendy H.; Parson, William W.; Sonnen, Joshua A.; Vu, Tiffany; Zheng, YunLin; Matsushita, Mark; Wolff, John; Lipe, Hillary; Bird, Thomas D.

    2010-01-01

    An X-linked myopathy was recently associated with mutations in the four-and-a-half-LIM domains 1 (FHL1) gene. We identified a family with late onset, slowly progressive weakness of scapuloperoneal muscles in three brothers and their mother. A novel missense mutation in the LIM2 domain of FHL1 (W122C) co-segregated with disease in the family. The phenotype was less severe than that in other reported families. Muscle biopsy revealed myopathic changes with FHL1 inclusions that were ubiquitin- and desmin-positive. This mutation provides additional evidence for X-linked myopathy caused by a narrow spectrum of mutations in FHL1, mostly in the LIM2 domain. Molecular dynamics (MD) simulations of the newly identified mutation and five previously published missense mutations in the LIM2 domain revealed no major distortions of the protein structure or disruption of zinc binding. There were, however, increases in the nonpolar, solvent-accessible surface area in one or both of two clusters of residues, suggesting that the mutant proteins have a variably increased propensity to aggregate. Review of the literature shows a wide range of phenotypes associated with mutations in FHL1. However, recognizing the typical scapuloperoneal phenotype and X-linked inheritance pattern will help clinicians arrive at the correct diagnosis. PMID:20633900

  15. Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clincal review with six additional families

    SciTech Connect

    Schrander-Stumpel, C.; Hoeweler, C.; Jones, M.

    1995-05-22

    X-linked hydrocephalus (HSAS) (MIM{sup *}307000), MASA syndrome (MIM {sup *}303350), and complicated spastic paraplegia (SPG1) (MIM {sup *}3129000) are closely related. Soon after delineation, SPG1 was incorporated into the spectrum of MASA syndrome. HSAS and MASA syndrome show great clinical overlap; DNA linkage analysis places the loci at Xq28. In an increasing number of families with MASA syndrome or HSAS, mutations in L1CAM, a gene located at Xq28, have been reported. In order to further delineate the clinical spectrum, we studied 6 families with male patients presenting with MASA syndrome, HSAS, or a mixed phenotype. We summarized data from previous reports and compared them with our data. Clinical variability appears to be great, even within families. Problems in genetic counseling and prenatal diagnosis, the possible overlap with X-linked corpus callosum agenesis and FG syndrome, and the different forms of X-linked complicated spastic paraplegia are discussed. Since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may be present in males with nonspecific mental retardation. We propose to abandon the designation MASA syndrome and use the term HSAS/MASA spectrum, incorporating SPG1. 79 refs., 6 figs., 2 tabs.

  16. Regional localization of an X-linked mental retardation gene to Xp21.1-Xp22.13 (MRX38)

    SciTech Connect

    Schutz, C.K.; Robinson, P.D.; White, B.N.

    1996-07-12

    A gene responsible for X-linked mental retardation with macrocephaly and seizures (MRX38) in a family with five affected males in three generations was localized to Xp21.1-p22.13 by linkage analysis. Recombination events placed the gene between DXS1226 distally and DXS1238 proximally, defining an interval of approximately 14 cM. A peak lod score of 2.71 was found with several loci in Xp21.1 (DXS992, DXS1236, DXS997, and DXS1036) at a recombination fraction of zero. The map intervals of 5 X-linked mental retardation loci, MRX2 (Xp22.1-p22.2), MRX19 (Xp22), MRX21 (Xp21.1-p22.3), MRX29 (Xp21.2-p22.1), and MRX32 (Xp21.2-p22.1), and two syndromal mental retardation loci, Partington syndrome (PRTS; Xp22) and Coffin-Lowry syndrome (CLS; Xp22.13-p22.2), overlap this region. As none of these display the same phenotype seen in the family reported here, this X-linked mental retardation locus may represent a new entity. 35 refs., 3 figs., 3 tabs.

  17. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.

    PubMed

    Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher's exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10-41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure

  18. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

    PubMed Central

    Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher’s exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10−41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal

  19. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.

    PubMed

    Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher's exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10-41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure

  20. Infantile dilated X-linked cardiomyopathy, G4.5 mutations, altered lipids, and ultrastructural malformations of mitochondria in heart, liver, and skeletal muscle.

    PubMed

    Bissler, John J; Tsoras, Monica; Göring, Harald H H; Hug, Peter; Chuck, Gail; Tombragel, Esther; McGraw, Catherine; Schlotman, James; Ralston, Michael A; Hug, George

    2002-03-01

    Mutations in the Xq28 gene G4.5 lead to dilated cardiomyopathy (DCM). Differential splicing of G4.5 results in a family of proteins called "tafazzins" with homology to acyltransferases. These enzymes assemble fatty acids into membrane lipids. We sequenced G4.5 in two kindreds with X-linked DCM and in two unrelated men, one with idiopathic DCM and the other with DCM of arrhythmogenic right ventricular dysplasia. We examined the ultrastructure of heart, liver, and muscle biopsy specimens in these three DCM types; we used gas chromatography to compare fatty acid composition in heart, liver, and muscle autopsy specimens of two patients of kindred 1 with that of controls. In X-linked DCM, G4.5 had a stop codon (E188X), a nonsense mutation, in kindred 1 and an amino acid substitution (G240R), a missense mutation, in kindred 2. In the two men with isolated DCM, G4.5 was not mutated. Ultrastructural mitochondrial malformations were present in the biopsy tissues of the patients with DCM. Cardiac biopsy specimens of both kindreds with X-linked DCM exhibited greatly enlarged mitochondria with large bundles of stacked, compacted, disarrayed cristae that differed from those of the two types of isolated DCM. Autopsy tissue of patients with X-linked DCM had decreased unsaturated and increased saturated fatty acid concentrations. Seven of 13 published G4.5 missense mutations, including the one presented here, occur in acyltransferase motifs. Impaired acyltransferase function could result in increased fatty acid saturation that would decrease membrane fluidity. Mitochondrial membrane proliferation may be an attempt to compensate for impaired function of acyltransferase. Cardiac ultrastructure separates X-linked DCM with G4.5 mutations from the two types of isolated DCM without G4.5 mutations. Electron microscopy of promptly fixed myocardial biopsy specimens has a role in defining the differential diagnosis of DCM. Mutational analysis of the G4.5 gene also serves this purpose.

  1. A review of canine pseudocyesis.

    PubMed

    Gobello, C; de la Sota, R L; Goya, R G

    2001-12-01

    The purpose of this article is to review the most relevant features of the physiology, clinical signs, diagnosis, treatment and prevention of canine pseudocyesis (PSC). This is a physiological syndrome, characterized by clinical signs such as: nesting, weight gain, mammary enlargement, lactation and maternal behaviour, which appears in non-pregnant bitches at the end of metaoestrus. PSC is a frequent finding in domestic dogs. Although it is generally admitted that prolactin (PRL) plays a central role in the appearance of PSC, its precise aetiophysiology is not completely understood yet. A number of clinical studies suggest that at some point of metaoestrus circulating PRL levels rise in overtly pseudopregnant bitches. Individual differences in sensitivity to PRL as well as the existence of molecular variants of canine PRL with different bioactivity versus immunoreactivity ratios may help clarify the aetiopathology of PSC. Diagnosis of PSC is based on the presence of typical clinical signs in metaoestrous non-pregnant bitches. Considering that PSC is a self limiting physiological state, mild cases usually need no treatment. Discouraging maternal behaviour and sometimes fitting Elizabethan collars to prevent licking of the mammary glands may suffice in these cases. Sex steroids (oestrogens, progestins and androgens) have been traditionally used to treat PSC but the side-effects usually outweigh the benefits of these medications. Inhibition of PRL release by ergot derivatives [bromocriptine (10-100 microg/kg per day for 10-14 days], cabergoline (5 microg/kg per day during 5-10 days), metergoline (0.2 mg/kg per day during 8-10 days) has proved to be effective for the treatment of canine PSC. Although some of these ergot derivatives present some untoward side-effects, they are transient and can usually be managed. Predisposed bitches not intended for breeding should be spayed as ovariectomy is the only permanent preventive measure.

  2. Neuroinflammation in advanced canine glaucoma

    PubMed Central

    Jiang, Bing; Harper, Matthew M.; Kecova, Helga; Adamus, Grazyna; Kardon, Randy H.; Grozdanic, Sinisa D.

    2010-01-01

    Purpose The pathophysiological events that occur in advanced glaucoma are not well characterized. The principal purpose of this study is to characterize the gene expression changes that occur in advanced glaucoma. Methods Retinal RNA was obtained from canine eyes with advanced glaucoma as well as from healthy eyes. Global gene expression patterns were determined using oligonucleotide microarrays and confirmed by real-time PCR. The presence of tumor necrosis factor (TNF) and its receptors was evaluated by immunolabeling. Finally, we evaluated the presence of serum autoantibodies directed against retinal epitopes using western blot analyses. Results We identified over 500 genes with statistically significant changes in expression level in the glaucomatous retina. Decreased expression levels were detected for large number of functional groups, including synapse and synaptic transmission, cell adhesion, and calcium metabolism. Many of the molecules with decreased expression levels have been previously shown to be components of retinal ganglion cells. Genes with elevated expression in glaucoma are largely associated with inflammation, such as antigen presentation, protein degradation, and innate immunity. In contrast, expression of many other pro-inflammatory genes, such as interferons or interleukins, was not detected at abnormal levels. Conclusions This study characterizes the molecular events that occur in the canine retina with advanced glaucoma. Our data suggest that in the dog this stage of the disease is accompanied by pronounced retinal neuroinflammation. PMID:21042562

  3. Canine size, shape, and bending strength in primates and carnivores.

    PubMed

    Plavcan, J Michael; Ruff, Christopher B

    2008-05-01

    Anthropoid primates are well known for their highly sexually dimorphic canine teeth, with males possessing canines that are up to 400% taller than those of females. Primate canine dimorphism has been extensively documented, with a consensus that large male primate canines serve as weapons for intrasexual competition, and some evidence that large female canines in some species may likewise function as weapons. However, apart from speculation that very tall male canines may be relatively weak and that seed predators have strong canines, the functional significance of primate canine shape has not been explored. Because carnivore canine shape and size are associated with killing style, this group provides a useful comparative baseline for primates. We evaluate primate maxillary canine tooth size, shape and relative bending strength against body size, skull size, and behavioral and demographic measures of male competition and sexual selection, and compare them to those of carnivores. We demonstrate that, relative to skull length and body mass, primate male canines are on average as large as or larger than those of similar sized carnivores. The range of primate female canine sizes embraces that of carnivores. Male and female primate canines are generally as strong as or stronger than those of carnivores. Although we find that seed-eating primates have relatively strong canines, we find no clear relationship between male primate canine strength and demographic or behavioral estimates of male competition or sexual selection, in spite of a strong relationship between these measures and canine crown height. This suggests either that most primate canines are selected to be very strong regardless of variation in behavior, or that primate canine shape is inherently strong enough to accommodate changes in crown height without compromising canine function.

  4. Congenital cataracts and other abnormalities in a female with 46.X, del(X)(q26q28)mat: A new locus for X-linked congenital cataract?

    SciTech Connect

    Babul, R.; Chitayat, D.; Teshima, I.

    1994-09-01

    Three forms of X-linked congenital cataracts have been delineated: congenital cataract with posterior Y-sutural opacities in heterozygotes, congenital cataract and microcornea or microphthalmia and congenital cataract-dental syndrome (Nance-Horan syndrome). Of these, only the Nance-Horan syndrome has been mapped to Xp22.3-p21.1. However, Warburg has suggested that these different forms of X-linked congenital cataracts are due to deletions of varying sizes, placing them in the vicinity of the Nance-Horan syndrome region. We report on a female patient born to a 29-year-old primigravida woman who at birth was found to have hypotonia, dysmorphic facial features, hydrocephalus and dense white congenital bilateral cataracts. Other ophthalmological findings included bilateral nystagmus and shallow orbits. Chromosome analysis revealed 46,X,del(X)(q26q28)mat. The mother, however, is phenotypically normal. Brain CT scan on the female infant revealed communicating hydrocephalus and a muscle biopsy showed congenital muscle fiber disproportion. An EMG and NCV were normal. At 4 years of age, her height and weight were below -3SD and her OFC was +2SD. Molecular studies using DNA markers located in Xq26-qter have revealed that the proximal breakpoint in the patient and her mother is defined by the HPRT locus while the distal breakpoint is defined by the locus DXS1108. This indicates that the deletion is not terminal but rather interstitial, retaining sequences proximal to the telomeric region. Other molecular studies are in progress to determine the X-inactivation status of the deleted chromosome in our patient and her mother as a possible explanation for the variation in the phenotype. These clinical and molecular findings suggest that another locus for X-linked congenital cataract exists at Xq26-28.

  5. Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry.

    PubMed

    Protasova, Maria S; Grigorenko, Anastasia P; Tyazhelova, Tatiana V; Andreeva, Tatiana V; Reshetov, Denis A; Gusev, Fedor E; Laptenko, Alexander E; Kuznetsova, Irina L; Goltsov, Andrey Y; Klyushnikov, Sergey A; Illarioshkin, Sergey N; Rogaev, Evgeny I

    2016-04-01

    X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders.

  6. The gene responsible for X-linked cleft palate (CPX) in a British Columbia native kindred is localized between PGK1 and DXYS1.

    PubMed Central

    Gorski, S M; Adams, K J; Birch, P H; Friedman, J M; Goodfellow, P J

    1992-01-01

    Human craniofacial malformations are a class of common congenital anomalies in which the etiology is heterogeneous and often poorly understood. To better delineate the molecular basis of craniofacial development, we have undertaken a series of experiments directed toward the isolation of a gene involved in human secondary palate formation. DNA marker linkage studies have been performed in a large British Columbia (B.C.) Native family in which cleft palate segregates as an X-linked trait. We have examined 62 family members, including 15 affected males and 8 obligate carrier females. A previous clinical description of the clefting defect in this kindred included submucous cleft palate and bifid or absent uvula. Our recent reevaluation of the family has indicated that ankyloglossia (tongue-tie) is also a feature of X-linked cleft palate in some of the affected males and carrier females. Ankyloglossia has previously been associated with X-linked cleft palate in an Icelandic kindred in which a gene responsible for cleft palate (CPX) was assigned to the Xq21.3-q22 region between DXYS12 and DXS17. For the B.C. kindred reported here, we have mapped the gene responsible for cleft palate and/or ankyloglossia to a more proximal position on the X chromosome. No recombination was observed between B.C. CPX and the DNA marker DXS72 (peak lod score [Zmax] = 7.44 at recombination fraction [theta] = .0) localized to Xq21.1. Recombination was observed between CPX and PGK1 (Zmax = 7.35 at theta = .03) and between CPX and DXYS1 (Zmax = 5.59 at theta = .04). These recombination events localize B.C. CPX between PGK1 and DXYS1 in the Xq13-q21.31 region. PMID:1570839

  7. Loss-of-function mutation in the X-linked TBX22 promoter disrupts an ETS-1 binding site and leads to cleft palate.

    PubMed

    Fu, Xiazhou; Cheng, Yibin; Yuan, Jia; Huang, Chunhua; Cheng, Hanhua; Zhou, Rongjia

    2015-02-01

    The cleft palate only (CPO) is a common congenital defect with complex etiology in humans. The molecular etiology of the CPO remains unknown. Here, we report a loss-of-function mutation in X-linked TBX22 gene (T-box 22) in a six-generation family of the CPO with obvious phenotypes of both cleft palate and hyper-nasal speech. We identify a functional -73G>A mutation in the promoter of TBX22, which is located at the core-binding site of transcription factor ETS-1 (v-ets avian erythroblastosis virus E26 oncogene homolog 1). Phylogenetic analysis showed that the sequence around the -73G>A mutation site is specific in primates. The mutation was detected in all five affected male members cosegregating with the affected phenotype and heterozygote occurred only in some unaffected females of the family, suggesting an X-linked transmission of the mutation in the family. The -73G>A variant is a novel single nucleotide mutation. Cell co-transfections indicated that ETS-1 could activate the TBX22 promoter. Moreover, EMSA and ChIP assays demonstrated that the allele A disrupts the binding site of ETS-1, thus markedly decreases the activity of the TBX22 promoter, which is likely to lead to the birth defect of the CPO without ankyloglossia. These results suggest that a loss-of-function mutation in the X-linked TBX22 promoter may cause the cleft palate through disruption of TBX22-ETS-1 pathway.

  8. An X-Linked Myopathy with Postural Muscle Atrophy and Generalized Hypertrophy, Termed XMPMA, Is Caused by Mutations in FHL1

    PubMed Central

    Windpassinger, Christian; Schoser, Benedikt; Straub, Volker; Hochmeister, Sonja; Noor, Abdul; Lohberger, Birgit; Farra, Natalie; Petek, Erwin; Schwarzbraun, Thomas; Ofner, Lisa; Löscher, Wolfgang N.; Wagner, Klaus; Lochmüller, Hanns; Vincent, John B.; Quasthoff, Stefan

    2008-01-01

    Summary We have identified a large multigenerational Austrian family displaying a novel form of X-linked recessive myopathy. Affected individuals develop an adult-onset scapulo-axio-peroneal myopathy with bent-spine syndrome characterized by specific atrophy of postural muscles along with pseudoathleticism or hypertrophy and cardiac involvement. Known X-linked myopathies were excluded by simple-tandem-repeat polymorphism (STRP) and single-nucleotide polymorphism (SNP) analysis, direct gene sequencing, and immunohistochemical analysis. STRP analysis revealed significant linkage at Xq25–q27.1. Haplotype analysis based on SNP microarray data from selected family members confirmed this linkage region on the distal arm of the X chromosome, thereby narrowing down the critical interval to 12 Mb. Sequencing of functional candidate genes led to the identification of a missense mutation within the four and a half LIM domain 1 gene (FHL1), which putatively disrupts the fourth LIM domain of the protein. Mutation screening of FHL1 in a myopathy family from the UK exhibiting an almost identical phenotype revealed a 3 bp insertion mutation within the second LIM domain. FHL1 on Xq26.3 is highly expressed in skeletal and cardiac muscles. Western-blot analysis of muscle biopsies showed a marked decrease in protein expression of FHL1 in patients, in concordance with the genetic data. In summary, we have to our knowledge characterized a new disorder, X-linked myopathy with postural muscle atrophy (XMPMA), and identified FHL1 as the causative gene. This is the first FHL protein to be identified in conjunction with a human genetic disorder and further supports the role of FHL proteins in the development and maintenance of muscle tissue. Mutation screening of FHL1 should be considered for patients with uncharacterized myopathies and cardiomyopathies. PMID:18179888

  9. A new X linked neurodegenerative syndrome with mental retardation, blindness, convulsions, spasticity, mild hypomyelination, and early death maps to the pericentromeric region

    PubMed Central

    Hamel, B.; Wesseling, P.; Renier, W.; van den Helm, B.; Ropers, H.; Kremer, H.; Mariman, E.

    1999-01-01

    We report on a family with an X linked neurodegenerative disorder consisting of mental retardation, blindness, convulsions, spasticity, and early death. Neuropathological examination showed mild hypomyelination. By linkage analysis, the underlying genetic defect could be assigned to the pericentromeric region of the X chromosome with a maximum lod score of 3.30 at θ=0.0 for the DXS1204 locus with DXS337 and PGK1P1 as flanking markers.


Keywords: XLMR; hypomyelination; early death; pericentromeric region PMID:10051014

  10. A computer programme for estimation of genetic risk in X linked disorders, combining pedigree and DNA probe data with other conditional information.

    PubMed Central

    Sarfarazi, M; Williams, H

    1986-01-01

    A computer programme is presented for calculating the recurrence risk in X linked disorders, combining pedigree and DNA probe data with other conditional information such as carrier detection tests. The methods of computation are shown in the given examples. The programme can be used with either a single DNA probe or two 'flanking' DNA probes for both familial and isolated case pedigrees. For isolated case families the mutation rate at the disease locus can be taken into account in conjunction with the DNA probe data. PMID:3754009

  11. JS-X syndrome: A multiple congenital malformation with vocal cord paralysis, ear deformity, hearing loss, shoulder musculature underdevelopment, and X-linked recessive inheritance.

    PubMed

    Hoeve, Hans L J; Brooks, Alice S; Smit, Liesbeth S

    2015-07-01

    We report on a family with a not earlier described multiple congenital malformation. Several male family members suffer from laryngeal obstruction caused by bilateral vocal cord paralysis, outer and middle ear deformity with conductive and sensorineural hearing loss, facial dysmorphisms, and underdeveloped shoulder musculature. The affected female members only have middle ear deformity and hearing loss. The pedigree is suggestive of an X-linked recessive inheritance pattern. SNP-array revealed a deletion and duplication on Xq28 in the affected family members. A possible aetiology is a neurocristopathy with most symptoms expressed in structures derived from branchial arches.

  12. Identification of a Novel Mutation in the CYBB Gene, p.Asp378Gly, in a Patient With X-linked Chronic Granulomatous Disease.

    PubMed

    Song, Sang-Mi; Park, Mi-Ran; Kim, Do-Soo; Kim, Jihyun; Kim, Yae-Jean; Ki, Chang-Seok; Ahn, Kangmo

    2014-07-01

    Chronic granulomatous disease (CGD) is a rare immunodeficiency disease, which is characterized by the lack of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. The disease presents leukocytosis, anemia, hypergammaglobulinemia, and granuloma formation of the skin, lung, or lymph nodes. The mutation of the CYBB gene encoding gp91phox, located on chromosome Xp21.1 is one of the causes of CGD. We report a patient with X-linked CGD who carried a novel mutation, a c.1133A>G (paAsp378Gly) missense mutation, in the CYBB gene. PMID:24991462

  13. Palmo-Plantar hyperkeratosis, intellectual disability, and spastic paraplegia in two maternal half brothers: further evidence for an X-linked inheritance.

    PubMed

    Isidor, Bertrand; Lefebvre, Tiphaine; Barbarot, Sébastien; Perrier, Julie; Mercier, Sandra; Péréon, Yann; Le Caignec, Cédric; David, Albert

    2013-06-01

    In 1983, Fitzsimmons et al. reported four brothers with an unrecognized disorder characterized by intellectual disability, spastic paraplegia, and palmo-plantar hyperkeratosis (OMIM 309500). In this report, we describe a family in which two males, maternal half-brothers, had learning disabilities. Both patients also showed spasticity in the lower limbs and palmo-plantar hyperkeratosis. The mother of the affected boys had learning difficulties but did not show any dermatological symptoms. This report confirms that the association of features reported by Fitzsimmons et al. is a distinct entity and further suggests an X-linked mode of inheritance.

  14. Linkage Disequilibrium for Two X-Linked Genes in Sardinia and Its Bearing on the Statistical Mapping of the Human X Chromosome

    PubMed Central

    Filippi, G.; Rinaldi, A.; Palmarino, R.; Seravalli, E.; Siniscalco, M.

    1977-01-01

    The distribution of four X-linked mutants (G6PD, Deutan, Protan and Xg) among lowland and once highly malarial populations of Sardinia discloses a clear-cut example of linkage disequilibrium between two of them (G6PD and Protan). In the same populations the distribution of G6PD-deficiency versus colorblindness of the Deutan type and the Xg blood-group is not significantly different from that expected at equilibrium. These data suggest indirectly that the loci for G6PD and Protan may be nearer to one another than those for G6PD and Deutan. PMID:301840

  15. Etiology of maxillary canine impaction: a review.

    PubMed

    Becker, Adrian; Chaushu, Stella

    2015-10-01

    This article is a review that enumerates the causes of impaction of the maxillary permanent canines, including hard tissue obstructions, soft tissue lesions, and anomalies of neighboring teeth, and discusses the much-argued relationship between environmental and genetic factors. These phenomena have been shown in many investigations to accompany the diagnosis of canine impaction and have been presented as unrelated anomalous features, each of which is etiologically construed as genetic, including the aberrant canine itself. While in general the influence of genetics pervades the wider picture, a guidance theory proposes an alternative etiologic line of reasoning and interpretation of these studies, in which the same genetically determined anomalous features provide an abnormal milieu in which the canine is reared and from which it is guided in its misdirected and often abortive path of eruption. PMID:26432311

  16. Canine atopic dermatitis - what have we learned?

    PubMed

    Nuttall, Tim; Uri, Maarja; Halliwell, Richard

    2013-02-23

    Canine atopic dermatitis is a complex multifactorial disease. Here, Tim Nuttall, Maarja Uri and Richard Halliwell, representing three generations of veterinary dermatologists, describe the research underpinning our understanding of the condition and highlight its relevance to clinical practice.

  17. [Nonsurgical endodontic treatment of an invaginated canine].

    PubMed

    Fernández Guerrero, F; Miñana Laliga, R; Bullon Fernandez, P

    1989-01-01

    We present a case of a maxillary canine with a dens invaginatus treated successfully. The patient had pain, swelling and a sinus tract coming from the inmature apex of the canine. The canals were enlarged and cleaned and the main canal was filled with Calcium Hydroxide to allow the root development. Seven months later, the patient was asymptomatic and the tooth was obturated with guttapercha. One year later it was confirm the success in the treatment.

  18. Proliferative histiocytic disorders of canine skin.

    PubMed

    Middleton, D J

    1997-06-01

    Proliferative histiocytic disorders of canine skin present a clinical spectrum from the innocuous self-limiting solitary dermal lesion of cutaneous histiocytoma, through the recurrent deep dermal nodules of cutaneous histiocytosis to the generally fatal condition of Bernese Mountain Dogs termed systemic histiocytosis, in which visceral involvement is commonly encountered. Immunocytochemical characterization of the constituent histiocytic cells and accompanying lymphoid infiltrate using canine species specific reagents has elucidated considerably the mechanism by which these conditions exhibit their various biologic behaviours.

  19. [Nonsurgical endodontic treatment of an invaginated canine].

    PubMed

    Fernández Guerrero, F; Miñana Laliga, R; Bullon Fernandez, P

    1989-01-01

    We present a case of a maxillary canine with a dens invaginatus treated successfully. The patient had pain, swelling and a sinus tract coming from the inmature apex of the canine. The canals were enlarged and cleaned and the main canal was filled with Calcium Hydroxide to allow the root development. Seven months later, the patient was asymptomatic and the tooth was obturated with guttapercha. One year later it was confirm the success in the treatment. PMID:2638021

  20. Environmental contamination by canine geohelminths

    PubMed Central

    2014-01-01

    Intestinal nematodes affecting dogs, i.e. roundworms, hookworms and whipworms, have a relevant health-risk impact for animals and, for most of them, for human beings. Both dogs and humans are typically infected by ingesting infective stages, (i.e. larvated eggs or larvae) present in the environment. The existence of a high rate of soil and grass contamination with infective parasitic elements has been demonstrated worldwide in leisure, recreational, public and urban areas, i.e. parks, green areas, bicycle paths, city squares, playgrounds, sandpits, beaches. This review discusses the epidemiological and sanitary importance of faecal pollution with canine intestinal parasites in urban environments and the integrated approaches useful to minimize the risk of infection in different settings. PMID:24524656

  1. Environmental contamination by canine geohelminths.

    PubMed

    Traversa, Donato; Frangipane di Regalbono, Antonio; Di Cesare, Angela; La Torre, Francesco; Drake, Jason; Pietrobelli, Mario

    2014-01-01

    Intestinal nematodes affecting dogs, i.e. roundworms, hookworms and whipworms, have a relevant health-risk impact for animals and, for most of them, for human beings. Both dogs and humans are typically infected by ingesting infective stages, (i.e. larvated eggs or larvae) present in the environment. The existence of a high rate of soil and grass contamination with infective parasitic elements has been demonstrated worldwide in leisure, recreational, public and urban areas, i.e. parks, green areas, bicycle paths, city squares, playgrounds, sandpits, beaches. This review discusses the epidemiological and sanitary importance of faecal pollution with canine intestinal parasites in urban environments and the integrated approaches useful to minimize the risk of infection in different settings. PMID:24524656

  2. CANINE: a robotic mine dog

    NASA Astrophysics Data System (ADS)

    Stancil, Brian A.; Hyams, Jeffrey; Shelley, Jordan; Babu, Kartik; Badino, Hernán.; Bansal, Aayush; Huber, Daniel; Batavia, Parag

    2013-01-01

    Neya Systems, LLC competed in the CANINE program sponsored by the U.S. Army Tank Automotive Research Development and Engineering Center (TARDEC) which culminated in a competition held at Fort Benning as part of the 2012 Robotics Rodeo. As part of this program, we developed a robot with the capability to learn and recognize the appearance of target objects, conduct an area search amid distractor objects and obstacles, and relocate the target object in the same way that Mine dogs and Sentry dogs are used within military contexts for exploration and threat detection. Neya teamed with the Robotics Institute at Carnegie Mellon University to develop vision-based solutions for probabilistic target learning and recognition. In addition, we used a Mission Planning and Management System (MPMS) to orchestrate complex search and retrieval tasks using a general set of modular autonomous services relating to robot mobility, perception and grasping.

  3. Biomarkers in canine parvovirus enteritis.

    PubMed

    Schoeman, J P; Goddard, A; Leisewitz, A L

    2013-07-01

    Canine parvovirus (CPV) enteritis has, since its emergence in 1978, remained a common and important cause of morbidity and mortality in young dogs. The continued incidence of parvoviral enteritis is partly due to the virus' capability to evolve into more virulent and resistant variants with significant local gastrointestinal and systemic inflammatory sequelae. This paper reviews current knowledge on historical-, signalment-, and clinical factors as well as several haematological-, biochemical- and endocrine parameters that can be used as diagnostic and prognostic biomarkers in CPV enteritis. These factors include season of presentation, purebred nature, bodyweight, vomiting, leukopaenia, lymphopaenia, thrombocytopaenia, hypercoagulability, hypercortisolaemia, hypothyroxinaemia, hypoalbuminaemia, elevated C-reactive protein and tumour necrosis factor, hypocholesterolaemia and hypocitrullinaemia. Factors contributing to the manifestations of CPV infection are multiple with elements of host, pathogen, secondary infections, underlying stressors and environment affecting severity and outcome. The availability of several prognosticators has made identification of patients at high risk of death and their subsequent targeted management more rewarding.

  4. Age estimation from canine volumes.

    PubMed

    De Angelis, Danilo; Gaudio, Daniel; Guercini, Nicola; Cipriani, Filippo; Gibelli, Daniele; Caputi, Sergio; Cattaneo, Cristina

    2015-08-01

    Techniques for estimation of biological age are constantly evolving and are finding daily application in the forensic radiology field in cases concerning the estimation of the chronological age of a corpse in order to reconstruct the biological profile, or of a living subject, for example in cases of immigration of people without identity papers from a civil registry. The deposition of teeth secondary dentine and consequent decrease of pulp chamber in size are well known as aging phenomena, and they have been applied to the forensic context by the development of age estimation procedures, such as Kvaal-Solheim and Cameriere methods. The present study takes into consideration canines pulp chamber volume related to the entire teeth volume, with the aim of proposing new regression formulae for age estimation using 91 cone beam computerized scans and a freeware open-source software, in order to permit affordable reproducibility of volumes calculation.

  5. Canine Cytogenetics - From band to basepair

    PubMed Central

    Breen, Matthew

    2008-01-01

    Humans and dogs have coexisted for thousands of years, during which time we have developed a unique bond, centered on companionship. Along the way, we have developed purebred dog breeds in a manner that has resulted unfortunately in many of them being affected by serious genetic disorders, including cancers. With serendipity and irony the unique genetic architecture of the 21st Century genome of Man's best friend may ultimately provide many of the keys to unlock some of nature's most intriguing biological puzzles. Canine cytogenetics has advanced significantly over the past 10 years, spurred on largely by the surge of interest in the dog as a biomedical model for genetic disease and the availability of advanced genomics resources. As such the role of canine cytogenetics has moved rapidly from one that served initially to define the gross genomic organization of the canine genome and provide a reliable means to determine the chromosomal location of individual genes, to one that enabled the assembled sequence of the canine genome to be anchored to the karyotype. Canine cytogenetics now presents the biomedical research community with a means to assist in our search for a greater understanding of how genome architectures altered during speciation and in our search for genes associated with cancers that affect both dogs and humans. The cytogenetics ‘toolbox’ for the dog is now loaded. This review aims to provide a summary of some of the recent advancements in canine cytogenetics. PMID:18467825

  6. [Panel of X-linked single-nucleotide polymorphic markers for DNA identification (XSNPid) based on multiplex genotyping by multilocus PCR and MALDI-TOF mass spectrometry].

    PubMed

    Stepanov, V A; Vagaitseva, K V; Kharkov, V N; Cherednichenko, A A; Bocharova, A V

    2016-01-01

    Human genetic markers linked with the X chromosome (X-linked) are used in the field of population and medical genetics, as well as for DNA identification of individuals in forensic science and forensic medicine. We proposed an XSNPid panel that consists of 66 unlinked single nucleotide X chromosome markers and developed a protocol for their multiplex genotyping using multilocus PCR and MALDI-TOF mass spectrometry. The XSNPid panel is genotyped within two multiplexes (36 and 30 markers). The developed protocol provides an efficient genotype reading; the fraction of determined genotypes is 98.29%. The high level of gene diversity (0.461) for the X-linked SNPs included in the panel is characteristic of the Russian population. A total of 63 out of 66 markers that provide a high efficiency of genotyping and independent inheritance are suitable for DNA identification purposes. The XSNPid panel is characterized by a very high discriminating ability when studying the Russian population. The probability of genotype coincidence in two unrelated individuals is 9 × 10^(-27) for women and 2 × 10^(-18) for men. Also, the XSNPid panel has a greater multiplex capacity in addition to a higher discriminating ability compared to the other closest analogues of the X chromosome SNP sets, which makes it more cost effective and less time consuming. The XSNPid panel is a convenient tool, not only for individual DNA identification, but also for population genetic studies. PMID:27414782

  7. Localization to Xq22 and clinical update of a family with X-linked recessive mental retardation with progression sensorineural deafness, progressive tapeto-retinal degeneration and dystonia

    SciTech Connect

    Tranebjaerg, L.; Schwartz, C.; Huggins, K.; Barker, D.; Stevenson, R.; Arena, J.F.; Gedde-Dahl, T.; Mikkelsen, M.; Mellgren, S.; Anderson, K. ||||

    1994-07-15

    In a reinvestigation of a six-generation Norwegian family, originally reported with non-syndromic X-linked recessive deafness by Mohr and Mageroy, we have demonstrated several syndromic manifestations. The 10 clinically characterized affected males range in age from 14-61 years, and show progressive mental deterioration and visual disability. Ophthalmological and electrophysiological studies showed myopia, decreased visual acuity, combined cone-rod dystrophy as well as central areolar dystrophy by means of ERG. Brain CT-scans showed cortical and central atrophy without predilection to specific areas. Linkage analysis, using X-chromosomal RFLPs and CA-repeats, yielded a maximum LOD score of 4.37 with linkage to DXS17. DXS17 is localized to Xq22. One recombinant with COL4A5 (deficient in Alport syndrome) was observed. Results from the studies of this family will be important in reclassification of non-syndromic X-linked deafness since the family now represents syndromic deafness and XLMR with a specific phenotype.

  8. Human X-linked Intellectual Disability Factor CUL4B Is Required for Post-meiotic Sperm Development and Male Fertility

    PubMed Central

    Lin, Chien-Yu; Chen, Chun-Yu; Yu, Chih-Hsiang; Yu, I-Shing; Lin, Shu-Rung; Wu, June-Tai; Lin, Ying-Hung; Kuo, Pao-Lin; Wu, Jui-Ching; Lin, Shu-Wha

    2016-01-01

    In this study, we demonstrate that an E3-ubiquitin ligase associated with human X-linked intellectual disability, CUL4B, plays a crucial role in post-meiotic sperm development. Initially, Cul4bΔ/Y male mice were found to be sterile and exhibited a progressive loss in germ cells, thereby leading to oligoasthenospermia. Adult Cul4b mutant epididymides also contained very low numbers of mature spermatozoa, and these spermatazoa exhibited pronounced morphological abnormalities. In post-meiotic spermatids, CUL4B was dynamically expressed and mitosis of spermatogonia and meiosis of spermatocytes both appeared unaffected. However, the spermatids exhibited significantly higher levels of apoptosis during spermiogenesis, particularly during the acrosome phase through the cap phase. Comparative proteomic analyses identified a large-scale shift between wild-type and Cul4b mutant testes during early post-meiotic sperm development. Ultrastructural pathology studies further detected aberrant acrosomes in spermatids and nuclear morphology. The protein levels of both canonical and non-canonical histones were also affected in an early spermatid stage in the absence of Cul4b. Thus, X-linked CUL4B appears to play a critical role in acrosomal formation, nuclear condensation, and in regulating histone dynamics during haploid male germ cell differentiation in relation to male fertility in mice. Thus, it is possible that CUL4B-selective substrates are required for post-meiotic sperm morphogenesis. PMID:26832838

  9. Mutational analysis of the biglycan gene excludes it as a candidate for x-linked dominant chondrodysplasia punctata, dyskeratosis congenita, and incontinentia pigmenti

    SciTech Connect

    Das, S.; Metzenberg, A.; Gitschier, J. ); Pai, G.S. )

    1994-05-01

    Biglycan is a small proteoglycan expressed mainly in cells of connective tissue, including chondrocytes, ostocytes, epithelial cells, and endothelial cells. The biglycan cDNA is 1,685 bp long. The biglycan gene was amplified in six segments by using nested PCR. Primers were synthesized to amplify exons 2-8 of the biglycan gene. Exon 1 was not amplified, as it consists entirely of 5[prime] untranslated sequence. Each exon was separately amplified, except for exons 5-7, which, because of their small size, were amplified in two segments and were subjected to SSCP analysis. Results indicate the presence of two different haplotypes for exon 2 and three different haplotypes for exon 4. Further SSCP analysis of control samples from nine females and one male confirmed that the exon 2 and exon 4 haplotypes consist of polymorphisms, rather than of mutations that specifically affect this patient population. Our results support recently described work that proposes that the biglycan gene may not be involved in X-linked dominant chondrodysplasia punctata. The absence of mutations in the biglycan gene in X-linked dominant chondrodysplasia punctata, dyskeratosis congenita, and incontinentia pigmenti suggest it is highly unlikely that mutations in this gene are responsible for any of these disorders.

  10. Successful allogeneic hematopoietic stem cell transplantation in a boy with X-linked inhibitor of apoptosis deficiency presenting with hemophagocytic lymphohistiocytosis: A case report

    PubMed Central

    Jiang, Ming-Yan; Guo, Xia; Sun, Shu-Wen; Li, Qiang; Zhu, Yi-Ping

    2016-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency.

  11. The Genetically Modified Polysialylated Form of Neural Cell Adhesion Molecule-Positive Cells for Potential Treatment of X-Linked Adrenoleukodystrophy

    PubMed Central

    Jang, Jiho; Kim, Han-Soo; Kang, Joon Won

    2013-01-01

    Purpose Cell transplantation of myelin-producing exogenous cells is being extensively explored as a means of remyelinating axons in X-linked adrenoleukodystrophy. We determined whether 3,3',5-Triiodo-L-thyronine (T3) overexpresses the ABCD2 gene in the polysialylated (PSA) form of neural cell adhesion molecule (NCAM)-positive cells and promotes cell proliferation and favors oligodendrocyte lineage differentiation. Materials and Methods PSA-NCAM+ cells from newborn Sprague-Dawley rats were grown for five days on uncoated dishes in defined medium with or without supplementation of basic fibroblast growth factor (bFGF) and/or T3. Then, PSA-NCAM+ spheres were prepared in single cells and transferred to polyornithine/fibronectin-coated glass coverslips for five days to determine the fate of the cells according to the supplementation of these molecules. T3 responsiveness of ABCD2 was analyzed using real-time quantitative polymerase chain reaction, the growth and fate of cells were determined using 5-bromo-2-deoxyuridine incorporation and immunocytochemistry, respectively. Results Results demonstrated that T3 induces overexpression of the ABCD2 gene in PSA-NCAM+ cells, and can enhance PSA-NCAM+ cell growth in the presence of bFGF, favoring an oligodendrocyte fate. Conclusion These results may provide new insights into investigation of PSA-NCAM+ cells for therapeutic application to X-linked adrenoleukodystrophy. PMID:23225827

  12. Monitoring of very long-chain fatty acids levels in X-linked adrenoleukodystrophy, treated with haematopoietic stem cell transplantation and Lorenzo's Oil.

    PubMed

    Stradomska, Teresa J; Drabko, Katarzyna; Moszczyńska, Elżbieta; Tylki-Szymańska, Anna

    2014-01-01

    X-linked adrenoleukodystrophy is a rare, neurodegenerative peroxisomal disorder connected with mutation in the ABCD1 gene, causing impairment of the peroxisomal β-oxidation process and in consequence, accumulation of very long-chain fatty acids (VLCFA) in blood and tissues. In this study we present serum very long-chain fatty acids levels during clinical course in an X-linked adrenoleukodystrophy patient after haematopoietic stem cell transplantation (HSCT) and on Lorenzo's Oil in a 11 years' period. The patient was diagnosed at the age of 8 months by family screening. The administration of LO was started at 2 years of age. HSCT from a family donor was performed twice. VLCFA serum levels were detected by the GC method. Chimaerism subsequent to HSCT was also analyzed. Increasing very long-chain fatty acids levels correlate with a decreasing chimaerism level after haematopoietic stem cell transplantation. The sequential monitoring of very long-chain fatty acids serum levels is important and useful for assessment of engraftment, graft failure or rejection.

  13. [Panel of X-linked single-nucleotide polymorphic markers for DNA identification (XSNPid) based on multiplex genotyping by multilocus PCR and MALDI-TOF mass spectrometry].

    PubMed

    Stepanov, V A; Vagaitseva, K V; Kharkov, V N; Cherednichenko, A A; Bocharova, A V

    2016-01-01

    Human genetic markers linked with the X chromosome (X-linked) are used in the field of population and medical genetics, as well as for DNA identification of individuals in forensic science and forensic medicine. We proposed an XSNPid panel that consists of 66 unlinked single nucleotide X chromosome markers and developed a protocol for their multiplex genotyping using multilocus PCR and MALDI-TOF mass spectrometry. The XSNPid panel is genotyped within two multiplexes (36 and 30 markers). The developed protocol provides an efficient genotype reading; the fraction of determined genotypes is 98.29%. The high level of gene diversity (0.461) for the X-linked SNPs included in the panel is characteristic of the Russian population. A total of 63 out of 66 markers that provide a high efficiency of genotyping and independent inheritance are suitable for DNA identification purposes. The XSNPid panel is characterized by a very high discriminating ability when studying the Russian population. The probability of genotype coincidence in two unrelated individuals is 9 × 10^(-27) for women and 2 × 10^(-18) for men. Also, the XSNPid panel has a greater multiplex capacity in addition to a higher discriminating ability compared to the other closest analogues of the X chromosome SNP sets, which makes it more cost effective and less time consuming. The XSNPid panel is a convenient tool, not only for individual DNA identification, but also for population genetic studies.

  14. High-resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X-linked blue cone monochromacy.

    PubMed

    Yatsenko, S A; Bakos, H A; Vitullo, K; Kedrov, M; Kishore, A; Jennings, B J; Surti, U; Wood-Trageser, M A; Cercone, S; Yatsenko, A N; Rajkovic, A; Iannaccone, A

    2016-01-01

    The human X chromosome contains ∼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases.

  15. Successful allogeneic hematopoietic stem cell transplantation in a boy with X-linked inhibitor of apoptosis deficiency presenting with hemophagocytic lymphohistiocytosis: A case report

    PubMed Central

    Jiang, Ming-Yan; Guo, Xia; Sun, Shu-Wen; Li, Qiang; Zhu, Yi-Ping

    2016-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency. PMID:27602064

  16. Mapping of a gene (MRXS9) for X-linked mental retardation, microcephaly, and variably short stature to Xq12-q21.31.

    PubMed

    Shrimpton, A E; Daly, K M; Hoo, J J

    1999-05-28

    Three boys from two families were identified as having a syndrome of X-linked mental retardation (XLMR) with microcephaly and short stature, clinically resembling Renpenning syndrome but with normal size of testicles in affected men. When the effort to map the gene for the above condition was initiated, it was realized that the two families were actually related to each other. Over 50 polymorphic markers of known locations along the X chromosome were scored in this family in a study to map the disease gene. Nine affected and four unaffected males were genotyped to produce a maximum LOD score of 4.42 at zero recombination with markers in proximal Xq. The results indicate that the gene responsible for this disorder is located in the cytogenetic Xq12 to Xq21.31 interval of the X chromosome within a section of chromosome of about 17 cM between the AR and DXS1217 loci over some 25 mb. Since the gene for the X-linked mental retardation from the original Saskatchewan family described by Renpenning [Renpenning et al., 1962: Can Med Assoc J 87:954-956; Fox and Gerrard, 1980: Am J Med Genet 7:491-495] was recently mapped to a different nonoverlapping region [Stevenson et al., 1998: Am J Hum Genet 62:1092-1101] this would appear to be a separate disorder.

  17. A new X-linked mental retardation (XLMR) syndrome with late-onset primary testicular failure, short stature and microcephaly maps to Xq25-q26.

    PubMed

    Cilliers, Deirdre D; Parveen, Rahat; Clayton, Peter; Cairns, Stephen A; Clarke, Sheila; Shalet, Stephen M; Black, Graeme C M; Newman, William G; Clayton-Smith, Jill

    2007-01-01

    X-linked mental retardation (XLMR) is a heterogeneous disorder with both syndromic and non-syndromic forms. Here we describe the clinical and molecular characterisation of a family with a syndromic form of XLMR with hypogonadism and short stature. We investigated a family in which four male members in two generations presented with hypergonadotrophic hypogonadism associated with development of small and abnormal testes. In two of the males, late-onset testicular ascent was noted. In addition, all affected males had short stature (<0.4th centile) and mild learning difficulties and three out of the four had microcephaly. Karyotypes were normal and endocrine investigations confirmed primary testicular failure. The phenotype segregated as an X-linked trait. Haplotype and genetic two-point linkage analysis with 22 microsatellites excluded the whole X chromosome except for a region on Xq25-Xq27 encompassing 13.7Mb with a maximum LOD score of 1.1 for marker DXS8038 at theta=0.05. One family previously described as having XLMR with hypogonadism and short stature maps to the same X chromosome region implicated in our family. However, the more severe mental retardation, muscle wasting and tremor described in this other family would suggest that our family is affected by a novel XLMR syndrome.

  18. Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness.

    PubMed

    Davidson, Alice E; Cheong, Sek-Shir; Hysi, Pirro G; Venturini, Cristina; Plagnol, Vincent; Ruddle, Jonathan B; Ali, Hala; Carnt, Nicole; Gardner, Jessica C; Hassan, Hala; Gade, Else; Kearns, Lisa; Jelsig, Anne Marie; Restori, Marie; Webb, Tom R; Laws, David; Cosgrove, Michael; Hertz, Jens M; Russell-Eggitt, Isabelle; Pilz, Daniela T; Hammond, Christopher J; Tuft, Stephen J; Hardcastle, Alison J

    2014-01-01

    We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES) and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT); however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS) overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP) (p = 6.81×10(-6)) on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk.

  19. Axonal Pathology Precedes Demyelination in a Mouse Model of X-Linked Demyelinating/ Type I Charcot-Marie Tooth (CMT1X) Neuropathy

    PubMed Central

    Vavlitou, Natalie; Sargiannidou, Irene; Markoullis, Kyriaki; Kyriacou, Kyriacos; Scherer, Steven S.; Kleopa, Kleopas A.

    2010-01-01

    X-linked Charcot-Marie-Tooth disease (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the gene that encodes the gap junction protein connexin32 (Cx32). Cx32 is expressed by myelinating Schwann cells and forms gap junctions in non-compact myelin areas but axonal involvement is more prominent in X-linked compared to other forms of demyelinating Charcot-Marie-Tooth disease. To clarify the cellular and molecular mechanisms of axonal pathology in CMT1X, we studied Gjb1-null mice at early stages (i.e. 2- to 4-month-old) of the neuropathy, when there is minimal or no demyelination. The diameters of large myelinated axons were progressively reduced in Gjb1-null mice compared to those in wild type littermates. Furthermore, neurofilaments were relatively more dephosphorylated and more densely packed starting at 2 months of age. Increased expression of β-amyloid precursor protein, a marker of axonal damage, was also detected in Gjb1-null nerves. Finally, fast axonal transport, assayed by sciatic nerve ligation experiments, was slower in distal axons of Gjb1-null vs. wild type animals with reduced accumulation of synaptic vesicle-associated proteins. These findings demonstrate that axonal abnormalities including impaired cytoskeletal organization and defects in axonal transport precede demyelination in this mouse model of CMT1-X. PMID:20720503

  20. Axonal pathology precedes demyelination in a mouse model of X-linked demyelinating/type I Charcot-Marie Tooth neuropathy.

    PubMed

    Vavlitou, Natalie; Sargiannidou, Irene; Markoullis, Kyriaki; Kyriacou, Kyriacos; Scherer, Steven S; Kleopa, Kleopas A

    2010-09-01

    The X-linked demyelinating/type I Charcot-Marie-Tooth neuropathy (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the gene that encodes the gap junction protein connexin32. Connexin32 is expressed by myelinating Schwann cells and forms gap junctions in noncompact myelin areas, but axonal involvement is more prominent in X-linked compared with other forms of demyelinating Charcot-Marie-Tooth disease. To clarify the cellular and molecular mechanisms of axonal pathology in CMT1X, we studied Gjb1-null mice at early stages (i.e. 2-4 months old) of the neuropathy, when there is minimal or no demyelination. The diameters of large myelinated axons were progressively reduced in Gjb1-null mice compared with those in wild-type littermates. Furthermore, neurofilaments were relatively more dephosphorylated and more densely packed starting at 2 months of age. Increased expression of β-amyloid precursor protein, a marker of axonal damage, was also detected in Gjb1-null nerves. Finally, fast axonal transport, assayed by sciatic nerve ligation experiments, was slower in distal axons of Gjb1-null versus wild-type animals with reduced accumulation of synaptic vesicle-associated proteins. These findings demonstrate that axonal abnormalities including impaired cytoskeletal organization and defects in axonal transport precede demyelination in this mouse model of CMT1X. PMID:20720503

  1. Expression of the genetic suppressor element 24.2 (GSE24.2) decreases DNA damage and oxidative stress in X-linked dyskeratosis congenita cells.

    PubMed

    Manguan-Garcia, Cristina; Pintado-Berninches, Laura; Carrillo, Jaime; Machado-Pinilla, Rosario; Sastre, Leandro; Pérez-Quilis, Carme; Esmoris, Isabel; Gimeno, Amparo; García-Giménez, Jose Luis; Pallardó, Federico V; Perona, Rosario

    2014-01-01

    The predominant X-linked form of Dyskeratosis congenita results from mutations in DKC1, which encodes dyskerin, a protein required for ribosomal RNA modification that is also a component of the telomerase complex. We have previously found that expression of an internal fragment of dyskerin (GSE24.2) rescues telomerase activity in X-linked dyskeratosis congenita (X-DC) patient cells. Here we have found that an increased basal and induced DNA damage response occurred in X-DC cells in comparison with normal cells. DNA damage that is also localized in telomeres results in increased heterochromatin formation and senescence. Expression of a cDNA coding for GSE24.2 rescues both global and telomeric DNA damage. Furthermore, transfection of bacterial purified or a chemically synthesized GSE24.2 peptide is able to rescue basal DNA damage in X-DC cells. We have also observed an increase in oxidative stress in X-DC cells and expression of GSE24.2 was able to diminish it. Altogether our data indicated that supplying GSE24.2, either from a cDNA vector or as a peptide reduces the pathogenic effects of Dkc1 mutations and suggests a novel therapeutic approach.

  2. High-resolution microarray analysis unravels complex Xq28 aberrations in patients and carriers affected by X-linked blue cone monochromacy

    PubMed Central

    Yatsenko, S.A.; Bakos, H.A.; Vitullo, K.; Kedrov, M.; Kishore, A.; Jennings, B.J.; Surti, U.; Wood-Trageser, M.A.; Cercone, S.; Yatsenko, A.N.; Rajkovic, A.; Iannaccone, A.

    2016-01-01

    The human X chromosome contains ~1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2–9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases. PMID:26153062

  3. Two novel DAX1 gene mutations in Chinese patients with X-linked adrenal hypoplasia congenita: clinical, hormonal and genetic analysis.

    PubMed

    Wu, C M; Zhang, H B; Zhou, Q; Wan, L; Jin, J; Ni, L; Pan, Y J; Wu, X Y; Ruan, L Y

    2011-09-01

    Mutations in the DAX1 gene result in X-linked congenital adrenal hypoplasia (AHC). Affected boys usually present with primary adrenal failure in early infancy or childhood and hypogonadotropic hypogonadism (HH) at puberty. This paper describes the clinical, hormonal, radiological, and genetic characteristics of 2 Chinese patients with X-linked AHC. Primary adrenal insufficiency occurred in the 2 patients during their childhood and HH was recognized at puberty. Genomic DNA was extracted from their peripheral blood leukocytes and coding sequence abnormalities of the DAX1 gene were assessed by PCR and direct sequencing analysis. Genetic analysis of the DAX1 gene revealed 2 novel mutations c.572-575 dupGGGC, p.Thr193Gly,fs,205X and c.773- 774 dupCC, p.Ser259Pro,fs,264X in exon 1, causing frameshifts and yeilding premature stop codons at 205 and 264, respectively. This study identifies 2 novel mutations in the DAX1 gene which can further expand the mutation database and benefit patients in the diagnosis and treatment of AHC. PMID:21270512

  4. RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa.

    PubMed

    Kirschner, R; Rosenberg, T; Schultz-Heienbrok, R; Lenzner, S; Feil, S; Roepman, R; Cremers, F P; Ropers, H H; Berger, W

    1999-08-01

    X-linked retinitis pigmentosa (XLRP) is a genetically heterogeneous group of progressive retinal degenerations. The disease process is initiated by premature apoptosis of rod photoreceptor cells in the retina, which leads to reduced visual acuity and, eventually, complete blindness. Mutations in the retinitis pigmentosa GTPase regulator ( RPGR ), a ubiquitously expressed gene at the RP3 locus in Xp21.1, account for approximately 20% of all X-linked cases. We have analysed the expression of this gene by northern blot hybridization, cDNA library screening and RT-PCR in various organs from mouse and man. These studies revealed at least 12 alternatively spliced isoforms. Some of the transcripts are tissue specific and contain novel exons, which elongate or truncate the previously reported open reading frame of the mouse and human RPGR gene. One of the newly identified exons is expressed exclusively in the human retina and mouse eye and contains a premature stop codon. The deduced polypeptide lacks 169 amino acids from the C-terminus of the ubiquitously expressed variant, including an isoprenylation site. Moreover, this exon was found to be deleted in a family with XLRP. Our results indicate tissue-dependent regulation of alternative splicing of RPGR in mouse and man. The discovery of a retina-specific transcript may explain why phenotypic abberations in RP3 are confined to the eye.

  5. X-linked neurodegenerative syndrome with congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration, linked to Xp22.33-pter

    SciTech Connect

    Portes, V. des; Beldjord, C.; Bruels, T.

    1996-07-12

    Linkage analysis was performed in a previously described family segregating for an X-linked progressive neurological disorder. In three generations, the disease was inherited from the mothers in seven affected males. Five had severe congenital hypotonia and died during the first year of life. Two other boys (maternal cousins) were found to have severe congenital ataxia, late-onset progressive myoclonic encephalopathy, and selective macular degeneration; brain CT-scan showed moderate cerebellar vermis hypoplasia. Linkage analysis was carried out in 12 informative relatives using 35 microsatellite markers (Genethon) evenly distributed on the X chromosome. A multipoint analysis showed a significant linkage (Z > 2) between the disease and three markers in the Xp22.33 region: DYS403 (Z = 2.37, {theta} = 0) which maps in the pseudoautosomal region, DXS7099 (Z = 2.45, {theta} = 0), and DXS7100 (Z = 2.48, {theta} = 0). Further linkage analysis with more telomeric markers will refine the location of this severe X-linked encephalopathy. 12 refs., 2 figs., 1 tab.

  6. The Mid2 X-linked Intellectual Disability Ubiquitin Ligase Associates with Astrin and Regulates Astrin Levels to Promote Cell Division

    PubMed Central

    Gholkar, Ankur A.; Senese, Silvia; Lo, Yu-Chen; Vides, Edmundo; Contreras, Ely; Hodara, Emmanuelle; Capri, Joseph; Whitelegge, Julian P.; Torres, Jorge Z.

    2015-01-01

    SUMMARY Mid1 and Mid2 are ubiquitin ligases that regulate microtubule dynamics and whose mutation is associated with X-linked developmental disorders. We show that Astrin, a microtubule-organizing protein, co-purifies with Mid1 and Mid2, has an overlapping localization with Mid1 and Mid2 at intercellular bridge microtubules, is ubiquitinated by Mid2 on lysine 409 and is degraded during cytokinesis. Mid2 depletion led to Astrin stabilization during cytokinesis, cytokinetic defects, multinucleated cells, and cell death. Similarly, expression of a K409A mutant Astrin in Astrin-depleted cells led to the accumulation of K409A on intercellular bridge microtubules and an increase in cytokinetic defects, multinucleated cells, and cell death. These results indicate that Mid2 regulates cell division through the ubiquitination of Astrin on K409, which is critical for its degradation and proper cytokinesis. These results may help explain how mutation of MID2 leads to misregulation of microtubule organization and the downstream disease pathology associated with X-linked intellectual disabilities. PMID:26748699

  7. The X-Linked-Intellectual-Disability-Associated Ubiquitin Ligase Mid2 Interacts with Astrin and Regulates Astrin Levels to Promote Cell Division.

    PubMed

    Gholkar, Ankur A; Senese, Silvia; Lo, Yu-Chen; Vides, Edmundo; Contreras, Ely; Hodara, Emmanuelle; Capri, Joseph; Whitelegge, Julian P; Torres, Jorge Z

    2016-01-12

    Mid1 and Mid2 are ubiquitin ligases that regulate microtubule dynamics and whose mutation is associated with X-linked developmental disorders. We show that astrin, a microtubule-organizing protein, co-purifies with Mid1 and Mid2, has an overlapping localization with Mid1 and Mid2 at intercellular bridge microtubules, is ubiquitinated by Mid2 on lysine 409, and is degraded during cytokinesis. Mid2 depletion led to astrin stabilization during cytokinesis, cytokinetic defects, multinucleated cells, and cell death. Similarly, expression of a K409A mutant astrin in astrin-depleted cells led to the accumulation of K409A on intercellular bridge microtubules and an increase in cytokinetic defects, multinucleated cells, and cell death. These results indicate that Mid2 regulates cell division through the ubiquitination of astrin on K409, which is critical for its degradation and proper cytokinesis. These results could help explain how mutation of MID2 leads to misregulation of microtubule organization and the downstream disease pathology associated with X-linked intellectual disabilities.

  8. Serological detection of infection with canine distemper virus, canine parvovirus and canine adenovirus in communal dogs from Zimbabwe.

    PubMed

    McRee, Anna; Wilkes, Rebecca P; Dawson, Jessica; Parry, Roger; Foggin, Chris; Adams, Hayley; Odoi, Agricola; Kennedy, Melissa A

    2014-01-01

    Domestic dogs are common amongst communities in sub-Saharan Africa and may serve as important reservoirs for infectious agents that may cause diseases in wildlife. Two agents of concern are canine parvovirus (CPV) and canine distemper virus (CDV), which may infect and cause disease in large carnivore species such as African wild dogs and African lions, respectively. The impact of domestic dogs and their diseases on wildlife conservation is increasing in Zimbabwe, necessitating thorough assessment and implementation of control measures. In this study, domestic dogs in north-western Zimbabwe were evaluated for antibodies to CDV, CPV, and canine adenovirus (CAV). These dogs were communal and had no vaccination history. Two hundred and twenty-five blood samples were collected and tested using a commercial enzyme-linked immunosorbent assay (ELISA) for antibodies to CPV, CDV, and CAV. Of these dogs, 75 (34%) had detectable antibodies to CDV, whilst 191 (84%) had antibodies to CPV. Antibodies to canine adenovirus were present in 28 (13%) dogs. Canine parvovirus had high prevalence in all six geographic areas tested. These results indicate that CPV is circulating widely amongst domestic dogs in the region. In addition, CDV is present at high levels. Both pathogens can infect wildlife species. Efforts for conservation of large carnivores in Zimbabwe must address the role of domestic dogs in disease transmission. PMID:25686382

  9. Serological detection of infection with canine distemper virus, canine parvovirus and canine adenovirus in communal dogs from Zimbabwe.

    PubMed

    McRee, Anna; Wilkes, Rebecca P; Dawson, Jessica; Parry, Roger; Foggin, Chris; Adams, Hayley; Odoi, Agricola; Kennedy, Melissa A

    2014-01-01

    Domestic dogs are common amongst communities in sub-Saharan Africa and may serve as important reservoirs for infectious agents that may cause diseases in wildlife. Two agents of concern are canine parvovirus (CPV) and canine distemper virus (CDV), which may infect and cause disease in large carnivore species such as African wild dogs and African lions, respectively. The impact of domestic dogs and their diseases on wildlife conservation is increasing in Zimbabwe, necessitating thorough assessment and implementation of control measures. In this study, domestic dogs in north-western Zimbabwe were evaluated for antibodies to CDV, CPV, and canine adenovirus (CAV). These dogs were communal and had no vaccination history. Two hundred and twenty-five blood samples were collected and tested using a commercial enzyme-linked immunosorbent assay (ELISA) for antibodies to CPV, CDV, and CAV. Of these dogs, 75 (34%) had detectable antibodies to CDV, whilst 191 (84%) had antibodies to CPV. Antibodies to canine adenovirus were present in 28 (13%) dogs. Canine parvovirus had high prevalence in all six geographic areas tested. These results indicate that CPV is circulating widely amongst domestic dogs in the region. In addition, CDV is present at high levels. Both pathogens can infect wildlife species. Efforts for conservation of large carnivores in Zimbabwe must address the role of domestic dogs in disease transmission.

  10. Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1)

    PubMed Central

    Caramins, Melody; Colebatch, James G.; Bainbridge, Matthew N.; Scherer, Steven S.; Abrams, Charles K.; Hackett, Emma L.; Freidin, Mona M.; Jhangiani, Shalini N.; Wang, Min; Wu, Yuanqing; Muzny, Donna M.; Lindeman, Robert; Gibbs, Richard A.

    2013-01-01

    We undertook a gene identification and molecular characterization project in a large kindred originally clinically diagnosed with SCA-X1. While presenting with ataxia, this kindred also had some unique peripheral nervous system features. The implicated region on the X chromosome was delineated using haplotyping. Large deletions and duplications were excluded by array comparative genomic hybridization. Exome sequencing was undertaken in two affected subjects. The single identified X chromosome candidate variant was then confirmed to co-segregate appropriately in all affected, carrier and unaffected family members by Sanger sequencing. The variant was confirmed to be novel by comparison with dbSNP, and filtering for a minor allele frequency of <1% in 1000 Genomes project, and was not present in the NHLBI Exome Sequencing Project or a local database at the BCM HGSC. Functional experiments on transfected cells were subsequently undertaken to assess the biological effect of the variant in vitro. The variant identified consisted of a previously unidentified non-synonymous variant, GJB1 p.P58S, in the Connexin 32/Gap Junction Beta 1 gene. Segregation studies with Sanger sequencing confirmed the presence of the variant in all affected individuals and one known carrier, and the absence of the variant in unaffected members. Functional studies confirmed that the p.P58S variant reduced the number and size of gap junction plaques, but the conductance of the gap junctions was unaffected. Two X-linked ataxias have been associated with genetic loci, with the first of these recently characterized at the molecular level. This represents the second kindred with molecular characterization of X-linked ataxia, and is the first instance of a previously unreported GJB1 mutation with a dominant and permanent ataxia phenotype, although different CNS deficits have previously been reported. This pedigree has also been relatively unique in its phenotype due to the presence of central and

  11. Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients

    PubMed Central

    Gu, Bai-Wei; Apicella, Marisa; Mills, Jason; Fan, Jian-Meng; Reeves, Dara A.; French, Deborah; Podsakoff, Gregory M.; Bessler, Monica; Mason, Philip J.

    2015-01-01

    Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by the presence of short telomeres at presentation. Mutations in ten different genes, whose products are involved in the telomere maintenance pathway, have been shown to cause DC. The X-linked form is the most common form of the disease and is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for the assembly and stability of telomerase and is also involved in ribosomal RNA (rRNA) processing where it converts specific uridines to pseudouridine. DC is thought to result from failure to maintain tissues, like blood, that are renewed by stem cell activity, but research into pathogenic mechanisms has been hampered by the difficulty of obtaining stem cells from patients. We reasoned that induced pluripotent stem (iPS) cells from X-linked DC patients may provide information about the mechanisms involved. Here we describe the production of iPS cells from DC patients with DKC1 mutations Q31E, A353V and ΔL37. In addition we constructed “corrected” lines with a copy of the wild type dyskerin cDNA expressed from the AAVS1 safe harbor locus. We show that in iPS cells with DKC1 mutations telomere maintenance is compromised with short telomere lengths and decreased telomerase activity. The degree to which telomere lengths are affected by expression of telomerase during reprograming, or with ectopic expression of wild type dyskerin, is variable. The recurrent mutation A353V shows the most severe effect on telomere maintenance. A353V cells but not Q31E or ΔL37 cells, are refractory to correction by expression of wild type DKC1 cDNA. Because dyskerin is involved in both telomere maintenance and ribosome biogenesis it has been postulated that defective ribosome biogenesis and translation may contribute to the disease phenotype. Evidence from mouse and zebra fish models has supported the involvement of ribosome biogenesis but primary cells from human

  12. [A case of X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome with repeated apnea attacks due to laryngomalacia].

    PubMed

    Ebishima, Yuko; Misaki, Takako; Owa, Kenji; Okuno, Takehiko; Wada, Takahito; Suehiro, Yutaka

    2013-01-01

    We report a case of X-linked alpha-thalassemia/mental retardation syndrome (ATR-X) with repeated apnea attacks dating from the patient's 12th year. We initially diagnosed them as obstructive apnea due to upper pharyngeal stenosis and laryngomalacia by polysomnography and laryngo-fiberscopy. However, reevaluation after one and a half years revealed that the boy had central and mixed apnea, as well as obstructive apnea. To date, few reports have been published on the causes of apnea attacks in ATR-X patients. We clinicians should therefore consider laryngomalacia as one cause of apnea attacks in ATR-X patients, and choose the appropriate therapy for a pattern of apnea that can change during its clinical course. PMID:23593745

  13. X-linked recessive congenital muscle fiber hypotrophy with central nuclei: abnormalities of growth and adenylate cyclase in muscle tissue cultures.

    PubMed

    Askanas, V; Engel, W K; Reddy, N B; Barth, P G; Bethlem, J; Krauss, D R; Hibberd, M E; Lawrence, J V; Carter, L S

    1979-10-01

    Muscle cells in cultures established from biopsy specimens of two children with an infantile-fatal form of X-linked recessive muscle fiber smallness with central nuclei showed an unusual ability to proliferate through numerous passages. Ultrastructurally, the cultured muscle fibers appeared very immature even after several weeks. The nuclei were large, the number of ribosomes was greatly increased, the myofibrils remained unstriated, and glycogen was accumulated in large lakes. The plasmalemma bound concanavalin A, alpha-bungarotoxin, and ruthenium red normally, but with tannic acid it did not show the dark binding of mature fibers. Biochemically, in the cultured muscle fibers, beta-adrenergic receptors were quantitatively normal. The level of adenylate cyclase in membranes was less than in cultured normal muscle; this defect could be responsible for impaired control mechanisms resulting in the other abnormalities observed.

  14. Prenatal molecular diagnosis of X-linked hydrocephalus via a silent C924T mutation in the L1CAM gene.

    PubMed

    Serikawa, Takehiro; Nishiyama, Kenichi; Tohyama, Jun; Tazawa, Ryushi; Goto, Kiyoe; Kuriyama, Yoko; Haino, Kazufumi; Kanemura, Yonehiro; Yamasaki, Mami; Nakata, Koh; Takakuwa, Koichi; Enomoto, Takayuki

    2014-11-01

    We present a case of a patient whose L1CAM gene in X-chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X-linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH.

  15. Prenatal molecular diagnosis of X-linked hydrocephalus via a silent C924T mutation in the L1CAM gene.

    PubMed

    Serikawa, Takehiro; Nishiyama, Kenichi; Tohyama, Jun; Tazawa, Ryushi; Goto, Kiyoe; Kuriyama, Yoko; Haino, Kazufumi; Kanemura, Yonehiro; Yamasaki, Mami; Nakata, Koh; Takakuwa, Koichi; Enomoto, Takayuki

    2014-11-01

    We present a case of a patient whose L1CAM gene in X-chromosome has a C924T transition. Her first son's ventriculomegaly was prenatally detected. A mature infant was born, his head circumference was large, and thumbs were bilaterally adducted. X-linked hydrocephalus (XLH) was suspected. The DNA examination revealed that both her and boy's LICAM gene had a C924T transition. She became pregnant 5 years later and amniocentesis was performed. The results of cytogenetic analysis revealed that the fetus was female. She continued her pregnancy and delivered a healthy girl. She again became pregnant 3 years later. The chromosomal analysis revealed that the fetus was male. Fetal DNA analysis determined that the fetus had the inherited mutation. She chose to terminate the pregnancy. A C924T mutation can be disease causing for XLH, and the detection of this mutation would aid in genetic counseling for the prenatal diagnosis of XLH. PMID:25039760

  16. The localization of a gene causing X-linked cleft palate and ankyloglossia (CPX) in an Icelandic kindred is between DXS326 and DXYS1X.

    PubMed

    Stanier, P; Forbes, S A; Arnason, A; Bjornsson, A; Sveinbjornsdottir, E; Williamson, R; Moore, G

    1993-09-01

    The locus responsible for X-linked, nonsyndromic cleft palate and/or ankyloglossia (CPX) has previously been mapped to the proximal long arm of the human X chromosome between Xq21.31 and q21.33 in an Icelandic kindred. We have extended these studies by analyzing an additional 14 informative markers in the family as well as including several newly investigated family members. Recombination analysis indicates that the CPX locus is more proximal than previously thought, within the interval Xq21.1-q21.31. Two recombinants place DXYS1X as the distal flanking marker, while one recombinant defines DXS326 as the proximal flanking marker, an interval of less than 5 cM. Each of the flanking markers recombines with the CPX locus, giving 2-point lod scores of Zmax = 4.16 at theta = 0.08 (DXS326) and Zmax = 5.80 at theta = 0.06 (DXYS1X).

  17. Syndromic form of X-linked mental retardation with marked hypotonia in early life, severe mental handicap, and difficult adult behavior maps to Xp22.

    PubMed

    Turner, Gillian; Gedeon, Agi; Kerr, Bronwyn; Bennett, Rachael; Mulley, John; Partington, Michael

    2003-03-15

    An X-linked recessive syndromic form of mental retardation is described in a family in which 10 males in four generations were affected. The main manifestations were severe to profound intellectual disability, muscular hypotonia in childhood, delayed walking, and difficult, aggressive behavior. There was a moderate reduction both in occipitofrontal circumference (OFC) and height and a similar facial appearance, triangular in shape with a high forehead, prominent ears, and a small pointed chin. Linkage analysis located the gene at Xp22 with maximum lod scores of 4.8 at theta = 0.0 for markers mapping between the closest recombination points at DXS7104 and DXS418. The physical length of this region is approximately 6 Mb. Mutations in the GRPR gene and M6b genes were excluded by sequence analysis. Nearby genes in which mutations are known to be associated with mental retardation (RPS6KA3, STK9, and VCXA, B and C), were excluded by position.

  18. Nuclear localized protein-1 (Nulp1) increases cell death of human osteosarcoma cells and binds the X-linked inhibitor of apoptosis protein

    SciTech Connect

    Steen, Hakan; Lindholm, Dan

    2008-02-08

    Nuclear localized protein-1 (Nulp1) is a recently identified gene expressed in mouse and human tissues particularly during embryonic development. Nulp1 belongs to the family of basic helix-loop-helix (bHLH) proteins that are important in development. The precise function of Nulp1 in cells is however not known. We observed that overexpression of Nulp1 induces a large increase in cell death of human osteosarcoma Saos2 cells with DNA fragmentation. In mouse N2A neuroblastoma cells Nulp1 affected cell proliferation and sensitized cells towards death induced by staurosporine. Staining using a novel antibody localized Nulp1 mainly to the cell nucleus and to some extent to the cytoplasm. Nulp1 binds the X-linked inhibitor of apoptosis protein (XIAP) and this interaction was increased during cell death. These results indicate that Nulp1 plays a role in cell death control and may influence tumor growth.

  19. Booster effect of canine distemper, canine parvovirus infection and infectious canine hepatitis combination vaccine in domesticated adult dogs.

    PubMed

    Taguchi, Masayuki; Namikawa, Kazuhiko; Maruo, Takuya; Orito, Kensuke; Lynch, Jonathan; Tsuchiya, Ryo; Sahara, Hiroeki

    2012-08-01

    Domesticated adult dogs with antibody titer classified as below 'high' to one or more of canine distemper virus (CDV), canine parvovirus type-2 (CPV-2) and canine adenovirus type-1 (CAdV-1) were then given an additional inoculation, and the effectiveness of this booster evaluated 2 months later. Consequently, CDV and CAdV-1 antibody titer experienced a significant increase, but the same effect was not observed in the antibody titer of CPV-2. These findings suggest that with additional inoculation, a booster effect may be expected in increasing antibody titers for CDV and CAdV-1, but it is unlikely to give an increase in CPV-2 antibody titer.

  20. Orthodontic Traction of Impacted Canine Using Cantilever

    PubMed Central

    Gonçalves, João Roberto; Cassano, Daniel Serra; Bianchi, Jonas

    2016-01-01

    The impaction of the maxillary canines causes relevant aesthetic and functional problems. The multidisciplinary approach to the proper planning and execution of orthodontic traction of the element in question is essential. Many strategies are cited in the literature; among them is the good biomechanical control in order to avoid possible side effects. The aim of this paper is to present a case report in which a superior canine impacted by palatine was pulled out with the aid of the cantilever on the Segmented Arch Technique (SAT) concept. A 14.7-year-old female patient appeared at clinic complaining about the absence of the upper right permanent canine. The proposed treatment prioritized the traction of the upper right canine without changing the occlusion and aesthetics. For this, it only installed the upper fixed appliance (Roth with slot 0.018), opting for SAT in order to minimize unwanted side effects. The use of cantilever to the traction of the upper right canine has enabled an efficient and predictable outcome, because it is of statically determined mechanics. PMID:27800192

  1. Epidemiologic study of canine blastomycosis in Wisconsin.

    PubMed

    Archer, J R; Trainer, D O; Schell, R F

    1987-05-15

    An epidemiologic study was designed to investigate the increasing number of cases of canine blastomycosis being reported in Wisconsin. From January 1980 through July 1982, 200 cases of canine blastomycosis from 39 Wisconsin counties were examined to assess epidemiologic and environmental aspects of this disease. Based on a survey of 176 dog owners, principal disease characteristics for canine blastomycosis were anorexia, lethargy, shortness of breath, chronic cough, and weight loss. The greatest number of cases of canine blastomycosis was in the northwest, north central, northeast, central, and southeast regions of Wisconsin. The northeast and central regions were determined to be new enzootic areas. Sporting breeds accounted for the largest percentage of cases among the various breeds of dogs in Wisconsin. Most of the affected dogs were 3 years old or younger and there was no apparent sexual predilection. Canine blastomycosis was diagnosed more frequently from late spring through late fall. Enzootic areas, except for the southeast region of Wisconsin, were located where the soil was sandy and acid. The results of this study suggested a possible association of enzootic areas with waterways, especially impoundments.

  2. Accounting for eXentricities: Analysis of the X Chromosome in GWAS Reveals X-Linked Genes Implicated in Autoimmune Diseases

    PubMed Central

    Chang, Diana; Gao, Feng; Slavney, Andrea; Ma, Li; Waldman, Yedael Y.; Sams, Aaron J.; Billing-Ross, Paul; Madar, Aviv; Spritz, Richard; Keinan, Alon

    2014-01-01

    Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies. PMID:25479423

  3. X-linked adrenal hypoplasia congenita: clinical and follow-up findings of two kindreds, one with a novel NR0B1 mutation.

    PubMed

    Pereira, Bernardo Dias; Pereira, Iris; Portugal, Jorge Ralha; Gonçalves, João; Raimundo, Luísa

    2015-04-01

    X-linked adrenal hypoplasia congenita typically manifests as primary adrenal insufficiency in the newborn age and hypogonadotropic hypogonadism in males, being caused by mutations in NR0B1 gene. We present the clinical and follow-up findings of two kindreds with NR0B1 mutations. The proband of kindred A had a diagnosis of primary adrenal insufficiency when he was a newborn. Family history was relevant for a maternal uncle death at the newborn age. Beyond 2 year-old steroid measurements rendered undetectable and delayed bone age was noticed. Molecular analysis of NR0B1 gene revealed a previously unreported mutation (c.1084A>T), leading to a premature stop codon, p.Lys362*, in exon 1. His mother and sister were asymptomatic carriers. At 14 year-old he had 3 mL of testicular volume and biochemical surveys (LH < 0.1 UI/L, total testosterone < 10 ng/dL) concordant with hypogonadotrophic hypogonadism. Kindred B had two males diagnosed with adrenal insufficiency at the newborn age. By 3 year-old both siblings had undetectable androgen levels and delayed bone age. NR0B1 molecular analysis identified a nonsense mutation in both cases, c.243C>G; p.Tyr81*, in exon 1. Their mother and sister were asymptomatic carriers. At 14 year-old (Tanner stage 1) hypothalamic-pituitary-gonadal axis evaluation in both males (LH < 0.1UI/L, total testosterone < 10 ng/dL) confirmed hypogonadotropic hypogonadism. In conclusion, biochemical profiles, bone age and an X-linked inheritance led to suspicion of NR0B1 mutations. Two nonsense mutations were detected in both kindreds, one previously unreported (c.1084A>T; p.Lys362*). Mutation identification allowed the timely institution of testosterone in patients at puberty and an appropriate genetic counselling for relatives.

  4. Identification and characterization of a novel X-linked AVPR2 mutation causing partial nephrogenic diabetes insipidus: a case report and review of the literature.

    PubMed

    Neocleous, Vassos; Skordis, Nicos; Shammas, Christos; Efstathiou, Elisavet; Mastroyiannopoulos, Nikolaos P; Phylactou, Leonidas A

    2012-07-01

    X-linked nephrogenic diabetes insipidus (NDI) is a rare disease characterized by a malfunctioning renal response to the antidiuretic hormone arginine vasopressin (AVP) due to mutations in the AVPR2 gene. A limited number of mutations in the AVPR2 gene resulting in partial phenotype have been described so far. In this mini-review the retrospective analysis of 13 known AVPR2 mutations that have been previously shown in vitro to partially abolish AVPR2 function is described, along with a novel mutation diagnosed in a kindred with partial NDI. In the present study, a 14 year old male and his 73 year old maternal grandfather were diagnosed with partial NDI based on the clinical phenotype, the water deprivation test and the inadequate response to 1-desamino-8-d-arginine vasopressin (DDAVP) administration. Sequencing analysis of the AVPR2 gene revealed the novel missense mutation p.N317S (g.1417A > G) in both patients. This mutation was re-created by site directed mutagenesis in an AVPR2 cDNA expression vector and was functionally characterized, in terms of arginine vasopressin (AVP) and DDAVP response. AVPR2 activity of the p.N317S mutant receptor after the AVP and DDAVP administration, as assessed by cAMP production was reduced and impaired when compared to cells that expressed the wild type AVPR2 gene. In conclusion, the affected members of this family have X-linked NDI with partial resistance to AVP, due to a missense mutation in the AVPR2 gene.

  5. Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome

    PubMed Central

    Kolanczyk, Mateusz; Krawitz, Peter; Hecht, Jochen; Hupalowska, Anna; Miaczynska, Marta; Marschner, Katrin; Schlack, Claire; Emmerich, Denise; Kobus, Karolina; Kornak, Uwe; Robinson, Peter N; Plecko, Barbara; Grangl, Gernot; Uhrig, Sabine; Mundlos, Stefan; Horn, Denise

    2015-01-01

    Ritscher-Schinzel syndrome (RSS)/3C (cranio-cerebro-cardiac) syndrome (OMIM#220210) is a rare and clinically heterogeneous developmental disorder characterized by intellectual disability, cerebellar brain malformations, congenital heart defects, and craniofacial abnormalities. A recent study of a Canadian cohort identified homozygous sequence variants in the KIAA0196 gene, which encodes the WASH complex subunit strumpellin, as a cause for a form of RSS/3C syndrome. We have searched for genetic causes of a phenotype similar to RSS/3C syndrome in an Austrian family with two affected sons. To search for disease-causing variants, whole-exome sequencing (WES) was performed on samples from two affected male children and their parents. Before WES, CGH array comparative genomic hybridization was applied. Validation of WES and segregation studies was done using routine Sanger sequencing. Exome sequencing detected a missense variant (c.1670A>G; p.(Tyr557Cys)) in exon 15 of the CCDC22 gene, which maps to chromosome Xp11.23. Western blots of immortalized lymphoblastoid cell lines (LCLs) from the affected individual showed decreased expression of CCDC22 and an increased expression of WASH1 but a normal expression of strumpellin and FAM21 in the patients cells. We identified a variant in CCDC22 gene as the cause of an X-linked phenotype similar to RSS/3C syndrome in the family described here. A hypomorphic variant in CCDC22 was previously reported in association with a familial case of syndromic X-linked intellectual disability, which shows phenotypic overlap with RSS/3C syndrome. Thus, different inactivating variants affecting CCDC22 are associated with a phenotype similar to RSS/3C syndrome. PMID:24916641

  6. Identification and characterization of a novel X-linked AVPR2 mutation causing partial nephrogenic diabetes insipidus: a case report and review of the literature.

    PubMed

    Neocleous, Vassos; Skordis, Nicos; Shammas, Christos; Efstathiou, Elisavet; Mastroyiannopoulos, Nikolaos P; Phylactou, Leonidas A

    2012-07-01

    X-linked nephrogenic diabetes insipidus (NDI) is a rare disease characterized by a malfunctioning renal response to the antidiuretic hormone arginine vasopressin (AVP) due to mutations in the AVPR2 gene. A limited number of mutations in the AVPR2 gene resulting in partial phenotype have been described so far. In this mini-review the retrospective analysis of 13 known AVPR2 mutations that have been previously shown in vitro to partially abolish AVPR2 function is described, along with a novel mutation diagnosed in a kindred with partial NDI. In the present study, a 14 year old male and his 73 year old maternal grandfather were diagnosed with partial NDI based on the clinical phenotype, the water deprivation test and the inadequate response to 1-desamino-8-d-arginine vasopressin (DDAVP) administration. Sequencing analysis of the AVPR2 gene revealed the novel missense mutation p.N317S (g.1417A > G) in both patients. This mutation was re-created by site directed mutagenesis in an AVPR2 cDNA expression vector and was functionally characterized, in terms of arginine vasopressin (AVP) and DDAVP response. AVPR2 activity of the p.N317S mutant receptor after the AVP and DDAVP administration, as assessed by cAMP production was reduced and impaired when compared to cells that expressed the wild type AVPR2 gene. In conclusion, the affected members of this family have X-linked NDI with partial resistance to AVP, due to a missense mutation in the AVPR2 gene. PMID:22386940

  7. Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens.

    PubMed

    Patat, Olivier; Pagin, Adrien; Siegfried, Aurore; Mitchell, Valérie; Chassaing, Nicolas; Faguer, Stanislas; Monteil, Laetitia; Gaston, Véronique; Bujan, Louis; Courtade-Saïdi, Monique; Marcelli, François; Lalau, Guy; Rigot, Jean-Marc; Mieusset, Roger; Bieth, Eric

    2016-08-01

    In 80% of infertile men with obstructive azoospermia caused by a congenital bilateral absence of the vas deferens (CBAVD), mutations are identified in the cystic fibrosis transmembrane conductance regulator gene (CFTR). For the remaining 20%, the origin of the CBAVD is unknown. A large cohort of azoospermic men with CBAVD was retrospectively reassessed with more stringent selection criteria based on consistent clinical data, complete description of semen and reproductive excurrent ducts, extensive CFTR testing, and kidney ultrasound examination. To maximize the phenotypic prioritization, men with CBAVD and with unilateral renal agenesis were considered ineligible for the present study. We performed whole-exome sequencing on 12 CFTR-negative men with CBAVD and targeted sequencing on 14 additional individuals. We identified three protein-truncating hemizygous mutations, c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), in ADGRG2, encoding the epididymal- and efferent-ducts-specific adhesion G protein-coupled receptor G2, in four subjects, including two related individuals with X-linked transmission of their infertility. Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility. Our study confirms the crucial role of ADGRG2 in human male fertility and brings new insight into congenital obstructive azoospermia pathogenesis. In men with CBAVD who are CFTR-negative, ADGRG2 testing could allow for appropriate genetic counseling with regard to the X-linked transmission of the molecular defect. PMID:27476656

  8. The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy

    PubMed Central

    Robusto, Michela; Fang, Mingyan; Asselta, Rosanna; Castorina, Pierangela; Previtali, Stefano C; Caccia, Sonia; Benzoni, Elena; De Cristofaro, Raimondo; Yu, Cong; Cesarani, Antonio; Liu, Xuanzhu; Li, Wangsheng; Primignani, Paola; Ambrosetti, Umberto; Xu, Xun; Duga, Stefano; Soldà, Giulia

    2015-01-01

    Next-generation sequencing is currently the technology of choice for gene/mutation discovery in genetically-heterogeneous disorders, such as inherited sensorineural hearing loss (HL). Whole-exome sequencing of a single Italian proband affected by non-syndromic HL identified a novel missense variant within the PRPS1 gene (NM_002764.3:c.337G>T (p.A113S)) segregating with post-lingual, bilateral, progressive deafness in the proband's family. Defects in this gene, encoding the phosphoribosyl pyrophosphate synthetase 1 (PRS-I) enzyme, determine either X-linked syndromic conditions associated with hearing impairment (eg, Arts syndrome and Charcot-Marie-Tooth neuropathy type X-5) or non-syndromic HL (DFNX1). A subsequent screening of the entire PRPS1 gene in 16 unrelated probands from X-linked deaf families led to the discovery of two additional missense variants (c.343A>G (p.M115V) and c.925G>T (p.V309F)) segregating with hearing impairment, and associated with mildly-symptomatic peripheral neuropathy. All three variants result in a marked reduction (>60%) of the PRS-I activity in the patients' erythrocytes, with c.343A>G (p.M115V) and c.925G>T (p.V309F) affecting more severely the enzyme function. Our data significantly expand the current spectrum of pathogenic variants in PRPS1, confirming that they are associated with a continuum disease spectrum, thus stressing the importance of functional studies and detailed clinical investigations for genotype–phenotype correlation. PMID:25182139

  9. Whole Genome Sequencing Reveals Novel Non-Synonymous Mutation in Ectodysplasin A (EDA) Associated with Non-Syndromic X-Linked Dominant Congenital Tooth Agenesis

    PubMed Central

    Sarkar, Tanmoy; Bansal, Rajesh; Das, Parimal

    2014-01-01

    Congenital tooth agenesis in human is characterized by failure of tooth development during tooth organogenesis. 300 genes in mouse and 30 genes in human so far have been known to regulate tooth development. However, candidature of only 5 genes viz. PAX9, MSX1, AXIN2, WNT10A and EDA have been experimentally established for congenitally missing teeth like hypodontia and oligodontia. In this study an Indian family with multiple congenital tooth agenesis was identified. Pattern of inheritance was apparently autosomal dominant type with a rare possibility to be X-linked. Whole genome sequencing of two affected individuals was carried out which revealed 119 novel non-synonymous single nucleotide variations (SNVs) distributed among 117 genes. Out of these only one variation (c.956G>T) located at exon 9 of X-linked EDA gene was considered as pathogenic and validated among all the affected and unaffected family members and unrelated controls. This variation leads to p.Ser319Ile change in the TNF homology domain of EDA (transcript variant 1) protein. In silico analysis predicts that this Ser319 is well conserved across different vertebrate species and a part of putative receptor binding site. Structure based homology modeling predicts that this amino acid residue along with four other amino acid residues nearby, those when mutated known to cause selective tooth agenesis, form a cluster that may have functional significance. Taken together these results suggest that c.956G>T (p.Ser319Ile) mutation plausibly reduces the receptor binding activity of EDA leading to distinct tooth agenesis in this family. PMID:25203534

  10. Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

    PubMed Central

    Twigg, Stephen R.F.; Babbs, Christian; van den Elzen, Marijke E.P.; Goriely, Anne; Taylor, Stephen; McGowan, Simon J.; Giannoulatou, Eleni; Lonie, Lorne; Ragoussis, Jiannis; Akha, Elham Sadighi; Knight, Samantha J.L.; Zechi-Ceide, Roseli M.; Hoogeboom, Jeannette A.M.; Pober, Barbara R.; Toriello, Helga V.; Wall, Steven A.; Rita Passos-Bueno, M.; Brunner, Han G.; Mathijssen, Irene M.J.; Wilkie, Andrew O.M.

    2013-01-01

    Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries—a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5′ untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5′ UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females. PMID:23335590

  11. First successful bone marrow transplantation for X-linked chronic granulomatous disease by using preimplantation female gender typing and HLA matching.

    PubMed

    Reichenbach, Janine; Van de Velde, Hilde; De Rycke, Martine; Staessen, Cathérine; Platteau, Peter; Baetens, Patricia; Güngör, Tayfun; Ozsahin, Hulya; Scherer, Franziska; Siler, Ulrich; Seger, Reinhard A; Liebaers, Inge

    2008-09-01

    Allogeneic hematopoietic stem cell transplantation from an human leukocyte antigen (HLA)-identical donor is currently the only proven curative treatment for chronic granulomatous disease. Hematopoietic stem cell transplantation with alternative donors is associated with higher morbidity and mortality. Therefore, we performed in vitro fertilization and preimplantation HLA matching combined with female sexing for hematopoietic stem cell transplantation in chronic granulomatous disease. Ethical and psychological issues were considered carefully. We used in vitro fertilization with X-enriched spermatozoa followed by preimplantation genetic diagnosis to identify female HLA-genoidentical embryos in a family in need of a suitable donor for their boy affected with severe X-linked chronic granulomatous disease. Two preimplantation genetic diagnosis cycles were performed in the family. In the second cycle, 2 HLA-genoidentical female embryos were transferred and a singleton pregnancy was obtained, resulting in the birth of an unaffected girl at term. Because of insufficient cell numbers in the cord-blood source, conventional hematopoietic stem cell transplantation had to be performed at 12 months of age of the donor and 5 years of age of the recipient and resulted in complete stable donor chimerism and immunologic reconstitution up to 25 months post-hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation after in vitro fertilization and combined female sexing and HLA matching offers a new and relatively rapid therapeutic option for patients with X-linked primary immunodeficiency such as chronic granulomatous disease who need hematopoietic stem cell transplantation but lack an HLA-genoidentical donor. PMID:18762514

  12. X-linked adrenal hypoplasia congenita: clinical and follow-up findings of two kindreds, one with a novel NR0B1 mutation.

    PubMed

    Pereira, Bernardo Dias; Pereira, Iris; Portugal, Jorge Ralha; Gonçalves, João; Raimundo, Luísa

    2015-04-01

    X-linked adrenal hypoplasia congenita typically manifests as primary adrenal insufficiency in the newborn age and hypogonadotropic hypogonadism in males, being caused by mutations in NR0B1 gene. We present the clinical and follow-up findings of two kindreds with NR0B1 mutations. The proband of kindred A had a diagnosis of primary adrenal insufficiency when he was a newborn. Family history was relevant for a maternal uncle death at the newborn age. Beyond 2 year-old steroid measurements rendered undetectable and delayed bone age was noticed. Molecular analysis of NR0B1 gene revealed a previously unreported mutation (c.1084A>T), leading to a premature stop codon, p.Lys362*, in exon 1. His mother and sister were asymptomatic carriers. At 14 year-old he had 3 mL of testicular volume and biochemical surveys (LH < 0.1 UI/L, total testosterone < 10 ng/dL) concordant with hypogonadotrophic hypogonadism. Kindred B had two males diagnosed with adrenal insufficiency at the newborn age. By 3 year-old both siblings had undetectable androgen levels and delayed bone age. NR0B1 molecular analysis identified a nonsense mutation in both cases, c.243C>G; p.Tyr81*, in exon 1. Their mother and sister were asymptomatic carriers. At 14 year-old (Tanner stage 1) hypothalamic-pituitary-gonadal axis evaluation in both males (LH < 0.1UI/L, total testosterone < 10 ng/dL) confirmed hypogonadotropic hypogonadism. In conclusion, biochemical profiles, bone age and an X-linked inheritance led to suspicion of NR0B1 mutations. Two nonsense mutations were detected in both kindreds, one previously unreported (c.1084A>T; p.Lys362*). Mutation identification allowed the timely institution of testosterone in patients at puberty and an appropriate genetic counselling for relatives. PMID:25993682

  13. Epidemiologic features of canine hypothyroidism.

    PubMed

    Milne, K L; Hayes, H M

    1981-01-01

    This study investigates the epidemiologic features of 3,206 dogs diagnosed with hypothyroidism (including myxedema) from 1.1 million dogs seen at 15 veterinary teaching hospitals between March, 1964 and June, 1978. Nine breeds found to be at high-risk for hypothyroidism were: golden retrievers, Doberman pinschers, dachshunds, Shetland sheepdogs, Irish setters, Pomeranians, miniature schnauzers, cocker spaniels, and Airedales. Two breed with a significant deficit of risk were German shepherds and mixed breed (mongrel) dogs. Age risk was greatest among younger dogs of high-risk breeds, further suggesting a genetic component to the etiology of this disease. In contrast, low-risk dogs had increasing relative risk through nine years of age. Spayed female dogs displayed a significantly higher risk when compared to intact females. Though not statistically significant, male castrated dogs had 30% more hypothyroidism compared to their intact counterparts. Among the case series were 91 endocrine and hormone-related neoplasms and 198 other endocrine-related disorders. Further studies linking canine hypothyroidism to other conditions, particularly cancer, could provide valuable insight into human disease experience.

  14. Canine rabies ecology in southern Africa.

    PubMed

    Bingham, John

    2005-09-01

    Rabies is a widespread disease in African domestic dogs and certain wild canine populations. Canine rabies became established in Africa during the 20th century, coinciding with ecologic changes that favored its emergence in canids. I present a conceptual and terminologic framework for understanding rabies ecology in African canids. The framework is underpinned by 2 distinct concepts: maintenance and persistence. Maintenance encompasses the notion of indefinite transmission of infection within a local population and depends on an average transmission ratio > or =1. Maintenance in all local populations is inherently unstable, and the disease frequently becomes extinct. Persistence, the notion of long-term continuity, depends on the presence of rabies in > or =1 local population within the canine metapopulation at any time. The implications for understanding rabies ecology and control are reviewed, as are previous studies on rabies ecology in African canids.

  15. Oncolytic Virotherapy of Canine and Feline Cancer

    PubMed Central

    Gentschev, Ivaylo; Patil, Sandeep S.; Petrov, Ivan; Cappello, Joseph; Adelfinger, Marion; Szalay, Aladar A.

    2014-01-01

    Cancer is the leading cause of disease-related death in companion animals such as dogs and cats. Despite recent progress in the diagnosis and treatment of advanced canine and feline cancer, overall patient treatment outcome has not been substantially improved. Virotherapy using oncolytic viruses is one promising new strategy for cancer therapy. Oncolytic viruses (OVs) preferentially infect and lyse cancer cells, without causing excessive damage to surrounding healthy tissue, and initiate tumor-specific immunity. The current review describes the use of different oncolytic viruses for cancer therapy and their application to canine and feline cancer. PMID:24841386

  16. Dens invaginatus (dilated odontome) in mandibular canine

    PubMed Central

    Halawar, Sangamesh S; Satyakiran, GVV; Krishnanand, PS; Prashanth, R

    2014-01-01

    Dens invaginatus is a developmental malformation of teeth related to shape of the teeth. Affected teeth show a deep infolding of enamel and dentin starting from the tip of the cusps and may extend deep into the root. It results from the invagination of the enamel organ into the dental papilla before calcification has occurred. Teeth most affected are maxillary lateral incisors. The presence of dens invaginatus in mandibular canine is extremely rare. The tooth was symptomatic in that it was mobile and was oriented horizontally. This article presents a case of symptomatic dens invaginatus in mandibular canine. PMID:25364169

  17. Medical Treatment of Primary Canine Glaucoma.

    PubMed

    Alario, Anthony F; Strong, Travis D; Pizzirani, Stefano

    2015-11-01

    Glaucoma is a painful and often blinding group of ocular diseases for which there is no cure. Although the definition of glaucoma is rapidly evolving, elevated intraocular pressure (IOP) remains the most consistent risk factor of glaucoma in the canine patient. Therapy should be aimed at neuroprotection. The mainstay of therapy focuses on reducing IOP and maintaining a visual and comfortable eye. This article discusses the most current ocular hypotensive agents, focusing on their basic pharmacology, efficacy at lowering IOP, and recommended use in the treatment of idiopathic canine glaucoma.

  18. Tubular vimentin metaplasia in canine nephropathies.

    PubMed

    Vilafranca, M; Domingo, M; Ferrer, L

    1994-09-01

    The expression of the intermediate filament vimentin was examined immunocytochemically in 17 cases of histologically confirmed primary canine nephropathy, and compared with its expression in normal canine kidney. In normal renal tissue, the expression of vimentin was restricted to glomerular elements, but in all cases of chronic interstitial nephritis it extended to the cortical tubular epithelia, and was correlated with the degree of tubulo-interstitial damage. Three of four cases of renal cell carcinoma had vimentin reactivity in neoplastic cells. In only one case of familial renal disease was vimentin expressed in scattered epithelial cells of the cortical tubules.

  19. A Study of Transmigrated Canine in an Indian Population

    PubMed Central

    Sharma, Gaurav; Nagpal, Archna

    2014-01-01

    Aim. The purpose of this study was to investigate the prevalence of transmigrated canines in a north Indian population and association with gender, side, associated pathologies, and dental anomalies. Subjects and methods. The prospective study consisted of panoramic radiographs of 3000 patients from two dental colleges in north India. The panoramic radiographs were screened for radiographically identified position of the transmigrated tooth, retained canine, and other coexisting dental anomalies. Results. The overall prevalence of transmigrated canines (15 mandibular and 5 maxillary) was 0.66%. The prevalence of mandibular transmigrated canine was 0.5% and maxillary transmigrated canine was 0.16%. All the transmigrated canines were unilateral. The age range was 15–53 years (average age 24.1 years) and there were 12 males (60%) and 8 females (40%). Type 1 mandibular canine transmigration was the commonest type found in our study (10 cases), followed by types 2 and 4 (2 cases each) and 1 case of type 5 transmigration. Conclusion. The prevalence of transmigrated canines in the north Indian population was 0.66% and no gender predilection was evident. The transmigrated canines have a low complication rate (10.0%) and no correlation with other dental anomalies was found. Type 3 canine is the rarest form of mandibular canine transmigration. PMID:27433532

  20. Canine parvovirus enteritis, canine distemper, and major histocompatibility complex genetic variation in Mexican wolves.

    PubMed

    Hedrick, Philip W; Lee, Rhonda N; Buchanan, Colleen

    2003-10-01

    The endangered Mexican wolf (Canis lupus baileyi) was recently reintroduced into Arizona and New Mexico (USA). In 1999 and 2000, pups from three litters that were part of the reintroduction program died of either canine parvovirus or canine distemper. Overall, half (seven of 14) of the pups died of either canine parvovirus or canine distemper. The parents and their litters were analyzed for variation at the class II major histocompatibility complex (MHC) gene DRB1. Similar MHC genes are related to disease resistance in other species. All six of the surviving pups genotyped for the MHC gene were heterozygous while five of the pups that died were heterozygous and one was homozygous. Resistance to pathogens is an important aspect of the management and long-term survival of endangered taxa, such as the Mexican wolf.

  1. Canine adenovirus downstream processing protocol.

    PubMed

    Puig, Meritxell; Piedra, Jose; Miravet, Susana; Segura, María Mercedes

    2014-01-01

    Adenovirus vectors are efficient gene delivery tools. A major caveat with vectors derived from common human adenovirus serotypes is that most adults are likely to have been exposed to the wild-type virus and exhibit active immunity against the vectors. This preexisting immunity limits their clinical success. Strategies to circumvent this problem include the use of nonhuman adenovirus vectors. Vectors derived from canine adenovirus type 2 (CAV-2) are among the best-studied representatives. CAV-2 vectors are particularly attractive for the treatment of neurodegenerative disorders. In addition, CAV-2 vectors have shown great promise as oncolytic agents in virotherapy approaches and as vectors for recombinant vaccines. The rising interest in CAV-2 vectors calls for the development of scalable GMP compliant production and purification strategies. A detailed protocol describing a complete scalable downstream processing strategy for CAV-2 vectors is reported here. Clarification of CAV-2 particles is achieved by microfiltration. CAV-2 particles are subsequently concentrated and partially purified by ultrafiltration-diafiltration. A Benzonase(®) digestion step is carried out between ultrafiltration and diafiltration operations to eliminate contaminating nucleic acids. Chromatography purification is accomplished in two consecutive steps. CAV-2 particles are first captured and concentrated on a propyl hydrophobic interaction chromatography column followed by a polishing step using DEAE anion exchange monoliths. Using this protocol, high-quality CAV-2 vector preparations containing low levels of contamination with empty viral capsids and other inactive vector forms are typically obtained. The complete process yield was estimated to be 38-45 %. PMID:24132487

  2. Lysis of human tumor cell lines by canine complement plus monoclonal antiganglioside antibodies or natural canine xenoantibodies.

    PubMed

    Helfand, S C; Hank, J A; Gan, J; Sondel, P M

    1996-01-10

    Because certain antiganglioside monoclonal antibodies can facilitate antibody-dependent cellular cytotoxicity against GD2+ ganglioside-bearing human and canine tumor cells, we wished to determine if clinically relevant antiganglioside monoclonal antibodies (Mabs) could also fix canine complement to lyse tumor cells in vitro. Using flow cytometry, human tumor cell lines (M21 melanoma and OHS osteosarcoma) were shown to highly express ganglioside GD2 and, to a lesser degree, GD3. In 51Cr release assays, M21 cells were lysed with canine serum, as a source of complement, plus either Mab 14.G2a or its mouse-human chimera, ch 14.18, specific for GD2. Heating canine serum abrogated its lytic activity and addition of rabbit complement reconstituted M21 lysis. Similar results were obtained with M21 cells when Mab R24 (against GD3) and canine serum were used. OHS cells were also lysed with canine serum plus Mab 14.G2a and lytic activity was abolished by heating canine serum but reconstituted with rabbit complement. Alone, canine serum or Mabs were not lytic to M21 or OHS cells. Conversely, human neuroblastoma (LAN-5) and K562 erythroleukemia cells were lysed by canine serum alone which was shown by flow cytometry to contain naturally occurring canine IgM antibodies that bound LAN-5 and K562 cells. The lytic activity of canine serum for LAN-5 or K562 cells was abolished by heating and restored by addition of either human or rabbit complement. Thus, human tumor cell lines can be lysed with antiganglioside Mabs through fixation and activation of canine complement-dependent lytic pathways. Canine xenoantibodies also mediate complement-dependent cytotoxicity of some human tumor cell lines. Together, these results are significant because they demonstrate an antitumor effect of the canine immune system which is of potential importance for cancer immunotherapy in a promising animal model.

  3. X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities

    PubMed Central

    Sikora, Jakub; Leddy, Jennifer; Gulinello, Maria; Walkley, Steven U.

    2016-01-01

    ABSTRACT Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably

  4. Metformin-induced mitochondrial function and ABCD2 up-regulation in X-linked adrenoleukodystrophy involves AMP-activated protein kinase.

    PubMed

    Singh, Jaspreet; Olle, Brittany; Suhail, Hamid; Felicella, Michelle M; Giri, Shailendra

    2016-07-01

    X-linked adrenoleukodystrophy (X-ALD) is a progressive neurometabolic disease caused by mutations/deletions in the Abcd1 gene. Similar mutations/deletions in the Abcd1 gene often result in diagonally opposing phenotypes of mild adrenomyeloneuropathy and severe neuroinflammatory cerebral adrenoleukodystrophy (ALD), which suggests involvement of downstream modifier genes. We recently documented the first evidence of loss of AMP-activated protein kinase α1 (AMPKα1) in ALD patient-derived cells. Here, we report the novel loss of AMPKα1 in postmortem brain white matter of patients with ALD phenotype. Pharmacological activation of AMPK can rescue the mitochondrial dysfunction and inhibit the pro-inflammatory response. The FDA approved anti-diabetic drug Metformin, a well-known AMPK activator, induces mitochondrial biogenesis and is documented for its anti-inflammatory role. We observed a dose-dependent activation of AMPKα1 in metformin-treated X-ALD patient-derived fibroblasts. Metformin also induced mitochondrial oxidative phosphorylation and ATP levels in X-ALD patient-derived fibroblasts. Metformin treatment decreased very long chain fatty acid levels and pro-inflammatory cytokine gene expressions in X-ALD patient-derived cells. Abcd2 [adrenoleukodystrophy protein-related protein] levels were increased in metformin-treated X-ALD patient-derived fibroblasts and Abcd1-KO mice primary mixed glial cells. Abcd2 induction was AMPKα1-dependent since metformin failed to induce Abcd2 levels in AMPKα1-KO mice-derived primary mixed glial cells. In vivo metformin (100 mg/Kg) in drinking water for 60 days induced Abcd2 levels and mitochondrial oxidative phosphorylation protein levels in the brain and spinal cord of Abcd1-KO mice. Taken together, these results provide proof-of-principle for therapeutic potential of metformin as a useful strategy for correcting the metabolic and inflammatory derangements in X-ALD by targeting AMPK. There is no effective therapy for inherited

  5. Metformin-induced mitochondrial function and ABCD2 up-regulation in X-linked adrenoleukodystrophy involves AMP-activated protein kinase.

    PubMed

    Singh, Jaspreet; Olle, Brittany; Suhail, Hamid; Felicella, Michelle M; Giri, Shailendra

    2016-07-01

    X-linked adrenoleukodystrophy (X-ALD) is a progressive neurometabolic disease caused by mutations/deletions in the Abcd1 gene. Similar mutations/deletions in the Abcd1 gene often result in diagonally opposing phenotypes of mild adrenomyeloneuropathy and severe neuroinflammatory cerebral adrenoleukodystrophy (ALD), which suggests involvement of downstream modifier genes. We recently documented the first evidence of loss of AMP-activated protein kinase α1 (AMPKα1) in ALD patient-derived cells. Here, we report the novel loss of AMPKα1 in postmortem brain white matter of patients with ALD phenotype. Pharmacological activation of AMPK can rescue the mitochondrial dysfunction and inhibit the pro-inflammatory response. The FDA approved anti-diabetic drug Metformin, a well-known AMPK activator, induces mitochondrial biogenesis and is documented for its anti-inflammatory role. We observed a dose-dependent activation of AMPKα1 in metformin-treated X-ALD patient-derived fibroblasts. Metformin also induced mitochondrial oxidative phosphorylation and ATP levels in X-ALD patient-derived fibroblasts. Metformin treatment decreased very long chain fatty acid levels and pro-inflammatory cytokine gene expressions in X-ALD patient-derived cells. Abcd2 [adrenoleukodystrophy protein-related protein] levels were increased in metformin-treated X-ALD patient-derived fibroblasts and Abcd1-KO mice primary mixed glial cells. Abcd2 induction was AMPKα1-dependent since metformin failed to induce Abcd2 levels in AMPKα1-KO mice-derived primary mixed glial cells. In vivo metformin (100 mg/Kg) in drinking water for 60 days induced Abcd2 levels and mitochondrial oxidative phosphorylation protein levels in the brain and spinal cord of Abcd1-KO mice. Taken together, these results provide proof-of-principle for therapeutic potential of metformin as a useful strategy for correcting the metabolic and inflammatory derangements in X-ALD by targeting AMPK. There is no effective therapy for inherited

  6. X-linked hypohidrotic ectodermal dysplasia: localization within the region Xq11-21.1 by linkage analysis and implications for carrier detection and prenatal diagnosis.

    PubMed Central

    Zonana, J; Clarke, A; Sarfarazi, M; Thomas, N S; Roberts, K; Marymee, K; Harper, P S

    1988-01-01

    X-linked hypohidrotic ectodermal dysplasia (H.E.D.) is a disorder of abnormal morphogenesis of ectodermal structures and is of unknown pathogenesis. Neither relatively accurate carrier detection nor prenatal diagnosis has been available. Previous localization of the disorder by linkage analysis utilizing restriction-fragment polymorphisms, by our group and others, has placed the disorder in the general pericentromeric region. We have extended our previous study by analyzing 36 families by means of 10 DNA probes at nine marker loci and have localized the disorder to the region Xq11-Xq21.1, probably Xq12-Xq13. Three loci--DXS159 (theta = .01, z = 14.84), PGK1 (theta = .02, z = 13.44), and DXS72 (theta = .02, z = 11.38)--show very close linkage to the disorder, while five other pericentromeric loci (DXS146, DXS14, DXYS1, DXYS2, and DXS3) display significant but looser linkage. Analysis of the linkage data yields no significant evidence for nonallelic heterogeneity for the X-linked form of the disorder. Both multipoint analysis and examination of multiply informative meioses with known phase establish that the locus for H.E.D. is flanked on one side by the proximal long arm loci DXYS1, DXYS2, and DXS3 and on the other side by the short arm loci DXS146 and DXS14. Multipoint mapping could not resolve the order of H.E.D. and the three tightly linked loci. This order can be inferred from published data on physical mapping of marker loci in the pericentromeric region, which have utilized somatic cell hybrid lines established from a female with severe manifestations of H.E.D., and an X/9 translocation (breakpoint Xq13.1). If one assumes that the breakpoint of the translocation is within the locus for H.E.D. and that there has not been a rearrangement in the hybrid line, then DXS159 would be proximal to the disorder and PGK1 and DXS72 would be distal to the disorder. Both accurate carrier detection and prenatal diagnosis are now feasible in a majority of families at risk for

  7. Experimental Forelimb Allotransplantation in Canine Model.

    PubMed

    Hong, Sa-Hyeok; Eun, Seok-Chan

    2016-01-01

    As reconstructive transplantation is gaining popularity as a viable alternative for upper limb amputees, it is becoming increasingly important for plastic surgeons to renew surgical skills and knowledge of this area. Forelimb allotransplantation research has been performed previously in rodent and swine models. However, preclinical canine forelimb allotransplantation studies are lacking in the literature. The purpose of this paper is to provide an overview of the surgical skills necessary to successfully perform forelimb transplantation in canines as a means to prepare for clinical application. A total of 18 transplantation operations on canines were performed. The recipient limb was shortened at the one-third proximal forearm level. The operation was performed in the following order: bones (two reconstructive plates), muscles and tendons (separately sutured), nerves (median, ulnar, and radial nerve), arteries (two), and veins (two). The total mean time of transplantation was 5 hours ± 30 minutes. All of the animals that received transplantation were treated with FK-506 (tacrolimus, 2 mg/kg) for 7 days after surgery. Most allografts survived with perfect viability without vascular problems during the early postoperative period. The canine forelimb allotransplantation model is well qualified to be a suitable training model for standard transplantation and future research work. PMID:27597952

  8. Experimental Forelimb Allotransplantation in Canine Model

    PubMed Central

    2016-01-01

    As reconstructive transplantation is gaining popularity as a viable alternative for upper limb amputees, it is becoming increasingly important for plastic surgeons to renew surgical skills and knowledge of this area. Forelimb allotransplantation research has been performed previously in rodent and swine models. However, preclinical canine forelimb allotransplantation studies are lacking in the literature. The purpose of this paper is to provide an overview of the surgical skills necessary to successfully perform forelimb transplantation in canines as a means to prepare for clinical application. A total of 18 transplantation operations on canines were performed. The recipient limb was shortened at the one-third proximal forearm level. The operation was performed in the following order: bones (two reconstructive plates), muscles and tendons (separately sutured), nerves (median, ulnar, and radial nerve), arteries (two), and veins (two). The total mean time of transplantation was 5 hours ± 30 minutes. All of the animals that received transplantation were treated with FK-506 (tacrolimus, 2 mg/kg) for 7 days after surgery. Most allografts survived with perfect viability without vascular problems during the early postoperative period. The canine forelimb allotransplantation model is well qualified to be a suitable training model for standard transplantation and future research work. PMID:27597952

  9. Canine models of human rare disorders

    PubMed Central

    Hytönen, Marjo K.

    2016-01-01

    ABSTRACT Millions of children worldwide are born with rare and debilitating developmental disorders each year. Although an increasing number of these conditions are being recognized at the molecular level, the characterization of the underlying pathophysiology remains a grand challenge. This is often due to the lack of appropriate patient material or relevant animal models. Dogs are coming to the rescue as physiologically relevant large animal models. Hundreds of spontaneous genetic conditions have been described in dogs, most with close counterparts to human rare disorders. Our recent examples include the canine models of human Caffey (SLC37A2), van den Ende-Gupta (SCARF2) and Raine (FAM20C) syndromes. These studies demonstrate the pathophysiological similarity of human and canine syndromes, and suggest that joint efforts to characterize both human and canine rare diseases could provide additional benefits to the advancement of the field of rare diseases. Besides revealing new candidate genes, canine models allow access to experimental resources such as cells, tissues and even live animals for research and intervention purposes. PMID:27803843

  10. Canine retraction with J hook headgear.

    PubMed

    Ayala Perez, C; de Alba, J A; Caputo, A A; Chaconas, S J

    1980-11-01

    Several methods have been described for accomplishing distal movement of canines without losing posterior anchorage. An accepted method in canine retraction is the use of headgear with J hooks. Since it incorporates extraoral anchorage, it is most effective in maximum-anchorage cases. It was the purpose of this study to analyze the distribution of force transmitted to the alveolus and surrounding structures by means of photoelastic visualization, utilizing J hook headgear for maxillary canine retraction. A three-dimensional model representing a human skull was used. This model was constructed with different birefringent materials to simulate bone, teeth, and periodontal membranes. Three different vectors of force were applied representing high-, medium-, and low-pull headgear, which were placed at angles of 40, 20, and 0 degrees to the occlusal plane. The photoelastic analysis was made by means of a circular-transmission polariscope arrangement, and the photoelastic data were recorded photographically. The stress areas created by the three different vectors of force were associated with various degrees of canine tipping. This effect was greater with the low-pull force component than with the medium-pull traction. The high-pull headgear produced the least tipping tendency, being closer to a bodily movemment effect. Further, stresses were transmitted to deeper structures of the simulated facial bones; these regions were the frontozygomatic, zygomaticomaxillary, and zygomaticotemporal sutures.

  11. Canine notoedric mange: a case report.

    PubMed

    Leone, Federico

    2007-04-01

    Notoedric mange is a cutaneous ectoparasitic disease of cats caused by Notoedres cati, a mite belonging to the Sarcoptidae family. The disease occurs in felids, occasionally in other mammals and in humans. The canine form, even if cited by some authors, has never been documented. This report describes for the first time a case of notoedric mange in a dog.

  12. Immune-mediated canine and feline keratitis.

    PubMed

    Andrew, Stacy E

    2008-03-01

    Although the normal cornea is devoid of vasculature and lymphatics, there are still several immune-mediated corneal conditions that can occur in dogs and cats. An overview of corneal immunology is presented. Diseases of dogs, including chronic superficial keratitis, superficial punctate keratitis, and canine adenovirus endotheliitis, as well as feline diseases, including eosinophilic keratitis and herpesvirus-related conditions, are discussed.

  13. Seroprevalence of Canine Distemper Virus in Cats

    PubMed Central

    Ikeda, Yasuhiro; Nakamura, Kazuya; Miyazawa, Takayuki; Chen, Ming-Chu; Kuo, Tzong-Fu; Lin, James A.; Mikami, Takeshi; Kai, Chieko; Takahashi, Eiji

    2001-01-01

    A seroepidemiological survey of canine distemper virus (CDV) infection in Asian felids revealed that the prevalence of antibodies varied depending on region and, in some cases, exposure to dogs. The serologic pattern in cats with antibodies indicated that they had likely been exposed to field strains rather than typical CDV vaccine strains. PMID:11329473

  14. Infectious canine hepatitis associated with prednisone treatment.

    PubMed

    Wong, Valerie M; Marche, Candace; Simko, Elemir

    2012-11-01

    An 11-week-old, female Alaskan husky dog housed outdoors in the Yukon, Canada, was diagnosed with infectious canine hepatitis. The predisposing factors in this puppy for such a rare disease included inappropriate vaccination program, potential contact with endemic wildlife, and immunosuppression due to prednisone treatment.

  15. X-Linked Agammaglobulinemia (XLA)

    MedlinePlus

    ... Patients Procedure for Accessing Lab Services Data Package Requirements AIDS Therapies Resource Guide In Vitro Efficacy Evaluations ... Assurances to Users Application and Approval Process User Requirements Malaria Vaccine Production Services Data Sharing and Release ...

  16. Mandibular canine dimensions as an aid in gender estimation

    PubMed Central

    Rajarathnam, Basetty Neelakantam; David, Maria Priscilla; Indira, Annamalai Ponnuswamy

    2016-01-01

    Background: All humans have an identity in life; compassionate societies require this identity to be recognized even after death. Objectives: To measure the dimensions of the mandibular canine and assess the usefulness of the mandibular canine as an aid in gender estimation. Materials and Methods: The study population comprised 200 subjects inclusive of 100 males and 100 females with an age range of 18–25 years. Measurements made in mm at the contact point were of mesiodistal width of the right and left canines and intercanine distance both intraorally and on casts, and the mandibular canine index (MCI) was calculated. The obtained data were subjected to t-test/Mann-Whitney test and discriminant function analysis. Results: All parameters of mandibular canines, namely, intercanine distance, canine width, and canine index were greater in males compared to females suggesting significant sexual dimorphism of mandibular canines. On subjecting the data to discriminant function analysis, it classified sex correctly in 73% of the samples. Conclusion: The result of our study establishes the existence of significant sexual dimorphism in mandibular canines. We can therefore, recommend the use of mandibular canine dimensions as an applicable and additional method for gender determination in human identification. PMID:27555724

  17. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation.

    PubMed

    Jensen, Lars Riff; Amende, Marion; Gurok, Ulf; Moser, Bettina; Gimmel, Verena; Tzschach, Andreas; Janecke, Andreas R; Tariverdian, Gholamali; Chelly, Jamel; Fryns, Jean-Pierre; Van Esch, Hilde; Kleefstra, Tjitske; Hamel, Ben; Moraine, Claude; Gecz, Jozef; Turner, Gillian; Reinhardt, Richard; Kalscheuer, Vera M; Ropers, Hans-Hilger; Lenzner, Steffen

    2005-02-01

    In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C, including one frameshift mutation and two nonsense mutations that introduce premature stop codons, as well as four missense mutations that alter evolutionarily conserved amino acids. In two of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families results from functional loss of the JARID1C protein. JARID1C (Jumonji AT-rich interactive domain 1C), formerly known as "SMCX," is highly similar to the Y-chromosomal gene JARID1D/SMCY, which encodes the H-Y antigen. The JARID1C protein belongs to the highly conserved ARID protein family. It contains several DNA-binding motifs that link it to transcriptional regulation and chromatin remodeling, processes that are defective in various other forms of mental retardation. Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function.

  18. Mutations in the JARID1C Gene, Which Is Involved in Transcriptional Regulation and Chromatin Remodeling, Cause X-Linked Mental Retardation

    PubMed Central

    Jensen, Lars Riff; Amende, Marion; Gurok, Ulf; Moser, Bettina; Gimmel, Verena; Tzschach, Andreas; Janecke, Andreas R.; Tariverdian, Gholamali; Chelly, Jamel; Fryns, Jean-Pierre; Van Esch, Hilde; Kleefstra, Tjitske; Hamel, Ben; Moraine, Claude; Gécz, Jozef; Turner, Gillian; Reinhardt, Richard; Kalscheuer, Vera M.; Ropers, Hans-Hilger; Lenzner, Steffen

    2005-01-01

    In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region. In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C, including one frameshift mutation and two nonsense mutations that introduce premature stop codons, as well as four missense mutations that alter evolutionarily conserved amino acids. In two of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families results from functional loss of the JARID1C protein. JARID1C (Jumonji AT-rich interactive domain 1C), formerly known as “SMCX,” is highly similar to the Y-chromosomal gene JARID1D/SMCY, which encodes the H-Y antigen. The JARID1C protein belongs to the highly conserved ARID protein family. It contains several DNA-binding motifs that link it to transcriptional regulation and chromatin remodeling, processes that are defective in various other forms of mental retardation. Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function. PMID:15586325

  19. The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain.

    PubMed

    Zhang, Chi; Mejia, Luis A; Huang, Ju; Valnegri, Pamela; Bennett, Eric J; Anckar, Julius; Jahani-Asl, Arezu; Gallardo, Gilbert; Ikeuchi, Yoshiho; Yamada, Tomoko; Rudnicki, Michael; Harper, J Wade; Bonni, Azad

    2013-06-19

    Intellectual disability is a prevalent disorder that remains incurable. Mutations of the X-linked protein PHF6 cause the intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS). However, the biological role of PHF6 relevant to BFLS pathogenesis has remained unknown. We report that knockdown of PHF6 profoundly impairs neuronal migration in the mouse cerebral cortex in vivo, leading to the formation of white matter heterotopias displaying neuronal hyperexcitability. We find that PHF6 physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies the PHF6 knockdown-induced migration phenotype in vivo. We also identify Neuroglycan C/Chondroitin sulfate proteoglycan 5 (NGC/CSPG5), a potential schizophrenia susceptibility gene, as a critical downstream target of PHF6 in the control of neuronal migration. These findings define PHF6, PAF1, and NGC/CSPG5 as components of a cell-intrinsic transcriptional pathway that orchestrates neuronal migration in the brain, with important implications for the pathogenesis of developmental disorders of cognition.

  20. A novel mutation in GJB1 (c.212T>G) in a Chinese family with X-linked Charcot-Marie-Tooth disease.

    PubMed

    Xiao, Fei; Tan, Jia-ze; Zhang, Xu; Wang, Xue-Feng

    2015-03-01

    Gap junction protein beta 1 (GJB1) gene mutations lead to X-linked Charcot-Marie-Tooth (CMTX) disease. We investigated a Chinese family with CMTX and identified a novel GJB1 point mutation. Clinical and electrophysiological features of the pedigree were examined, and sequence alterations of the coding region of GJB1 that encode connexin32 were determined by direct sequencing. Sequence alignment of the mutation site was performed using Clustal W. Mutation effects were analysed using PolyPhen-2, SIFT and Mutation Taster software. The three-dimensional structures of the mutant and wild-type proteins were predicted by modeling with SWISS MODEL online software. The affected family members displayed typical Charcot-Marie-Tooth phenotypes, but phenotypic heterogeneity was observed. Nerve conduction velocities of all affected patients were slow. Sequencing of GJB1 revealed a heterozygous T>G missense mutation at nucleotide 212 in the proband, the proband's mother and the proband's daughter. The affected male sibling of the proband displayed a hemizygous missense mutation with T>G transition at the identical position on the GJB1 gene. This mutation resulted in an amino acid change from isoleucine to serine that was predicted to lead to tertiary structural alterations that would disrupt the function of the GJB1 protein. A novel point mutation in GJB1 was detected, expanding the spectrum of GJB1 mutations known to be associated with CMTX.